FR3074422A1 - PH 7 INJECTABLE SOLUTION COMPRISING AT LEAST ONE BASIC INSULIN WITH A PI BETWEEN 5.8 AND 8.5 AND A CO-POLYAMINOACIDE CARRYING CARBOXYLATE LOADS AND HYDROPHOBIC RADICALS - Google Patents

Abstract

The invention relates to a physically stable composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least: a) a basal insulin whose isoelectric point (pi) is between 5.8 and 8.5 and b) a co-polyamino acid of formula IQ [Hy] j [PLG] k Formula I Wherein: j ≥ 1; k≥ 2

Description

PH 7 INJECTION SOLUTION COMPRISING AT LEAST ONE BASAL INSULIN OF WHICH

THE PI IS BETWEEN 5.8 AND 8.5 AND A CO-POLYAMINOACID CARRIER OF

CARBOXYLATE AND HYDROPHOBIC RADICAL CHARGES The invention relates to insulin injection therapy (s) for treating diabetes.

The invention 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 one basal insulin whose isoelectric point (pl) is between 5.8 and 8.5 and a co-polyamino acid carrying carboxylate charges and hydrophobic radicals.

Insulin therapy, or diabetes therapy by insulin injection, has seen remarkable progress in recent years thanks in particular to the development of new insulins offering better correction of patients' blood sugar compared to insulin human and which better simulate the physiological activity of the pancreas.

When type II diabetes is diagnosed in a patient, a gradual treatment is put in place. The patient first takes oral anti-diabetics (OAD) such as Metformin. When the OADs alone are no longer sufficient to regulate the level of glucose in the blood, a change in treatment must be made and, depending on the specificities of the patients, different combinations of treatments can be implemented. The patient may for example have a treatment based on a basal insulin such as insulin glargine or insulin detemir in addition to the OADs, then then depending on the evolution of the pathology a treatment based on basal insulin and insulin prandial.

[0005] Furthermore, today, to ensure the transition from treatments with OADs, when these are no longer able to control the level of glucose in the blood, towards a basal insulin / mealtime insulin treatment, GLP-1 RA analog injection is recommended.

GLP-1 RA for agonists of the Glucagon-Like Peptide-1 receptor, are insulinotropic or incretin peptides, and belong to the family of gastrointestinal hormones (or Gut Hormones) which stimulate insulin secretion when the blood sugar is too high, for example after a meal.

[0007] The gastrointestinal hormones (Gut hormones) are also called satiety hormones. They include in particular GLP-1 RA (Glucagon Iike peptide1 receptor agonist) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon), YY peptide, amylin, cholecystokinin, pancreatic polypeptide (PP), ghreline and enterostatin which have peptide or protein structures. They also stimulate the secretion of insulin in response to glucose and fatty acids and are therefore potential candidates for the treatment of diabetes.

Among these, GLP-1 RA are those which have brought to date the best results in the development of drugs. They have allowed patients with type II diabetes to lose weight while having better control of their blood sugar.

Analogs or derivatives of GLP-1 RA have thus been developed in particular to improve their stability.

On the other hand, to cover his daily insulin needs, a diabetic patient currently has, schematically, two types of insulins having complementary actions: prandial insulins (or so-called fast-acting insulins) and basal insulins (or so-called slow-acting insulins).

Prandial insulins allow rapid management (metabolization and / or storage) of the glucose supplied during meals and snacks. The patient must inject a meal insulin before each food intake, approximately 2 to 3 injections per day. The most widely used prandial insulins are: recombinant human insulin, NovoLog® (insulin aspart from NOVO NORDISK), Humalog® (insulin lispro from ELI LILLY) and Apidra® (insulin glulisine from SANOFI).

Basal insulins maintain the patient's glycemic homeostasis, outside of periods of food intake. They act mainly to block endogenous glucose production (hepatic glucose). The daily basal insulin dose generally corresponds to 40-50% of the total daily insulin requirements. Depending on the basal insulin used, this dose is given in 1 or 2 injections, regularly distributed throughout the day. The most commonly used basal insulins are Levemir® (insulin detemir from NOVO NORDISK) and Lantus® (insulin glargine from SANOFI).

It will be noted to be exhaustive that NPH (insulin NPH for Neutral Prôtamine Hagedorn; Humuline NPH®, Insulatard®) is the oldest basal insulin. This formulation is the result of a precipitation of human insulin (anionic at neutral pH) by a cationic protein, the premamine. The microcrystals thus formed are dispersed in an aqueous suspension and dissolve slowly after subcutaneous injection. This slow dissolution ensures a prolonged release of insulin. However, this release does not ensure a constant concentration of insulin over time. The release profile is bell-shaped and lasts only between 12 and hours. It is therefore injected twice a day. This NPH basal insulin is much less efficient than modern basal insulins, Levemir® and Lantus®. NPH is a basal acting insulin.

The principle of NPH has evolved with the appearance of rapid analog insulins to give products called "Premix" offering both rapid action and intermediate action. NovoLog Mix® (NOVO NOR.DISK) and Humalog Mix® (ELI LILLY) are formulations comprising a rapid analogue insulin, Novolog® and Humalog®, partially complexed by protamine. These formulations thus contain microcrystals of analogous insulin, the action of which is said to be intermediate, and a portion of insulin that remains soluble, the action of which is rapid. These formulations offer the advantage of a fast insulin but they also have the defect of NPH, i.e. a duration of action limited between 12 and 16 hours and an insulin released in a “bell”. However, these products allow the patient to inject a basal intermediate acting insulin with a fast acting prandial insulin at one time. Many patients are anxious to reduce their number of injections.

The basal insulins currently marketed can be classified according to the technical solution which allows the prolonged action to be obtained and to date two approaches are used.

The first, that of insulin detemir is the binding to albumin in vivo. It is an analog, soluble at pH 7, which comprises a fatty acid side chain (tetradecanoyl) attached to position B29 which, in vivo, allows this insulin to associate with albumin. Its prolonged action is mainly due to this affinity for albumin after subcutaneous injection.

However, its pharmacokinetic profile does not cover a day, which means that it is most often used in two injections per day.

Another soluble insulin at pH 7 is insulin degludec sold under the name Tresiba® ^d . It also includes a fatty acid side chain attached to insulin (hexadecandioyl-yL-Glu).

The second, that of insulin glargine, is precipitation at physiological pH. Insulin glargine is an analogue of human insulin obtained by elongation of the C-terminal part of the B chain of human insulin with two arginine residues, and by substitution of the asparagine A21 residue with a glycine residue (US 5,656,722). The addition of two residues of arginine was thought to adjust the pi (isoelectric point) of insulin glargine to physiological pH, and thus make this analog of human insulin insoluble in physiological medium.

Also, the substitution of ΓΑ21 has been designed in order to make insulin glargine stable at acidic pH and thus able to formulate it in the form of a solution for injection at acidic pH. During subcutaneous injection, the passage of insulin glargine from an acidic pH (pH 4-4.5) to a physiological pH (neutral pH) causes its precipitation under the skin. The slow redissolution of the insulin glargine micro-particles ensures a slow and proionged action.

The hypoglycemic effect of insulin glargine is almost constant over a period of 24 hours, which allows most patients to limit themselves to one injection per day.

Insulin glargine is considered today as the most used basal insulin.

However, the necessarily acidic pH of basal insulin formulations, the isoelectric point of which is between 5.8 and 8.5, of the insulin glargine type, can be a real drawback, because this acidic pH of the formulation of insulin glargine sometimes causes pain in patients with injection and especially prevents any formulation with other proteins and in particular with meal insulin because the latter are not stable at acidic pH. The impossibility of formulating a prandial insulin, at acidic pH, results from the fact that a prandial insulin undergoes, under these conditions, a deamidation secondary reaction in position A21, which does not make it possible to meet the stability requirements applicable to medicinal products. injectables.

To date, in applications WO 2013/021143 A1, WO 2013/104861 A1, WO 2014/124994 A1 and WO 2014/124993 A1 it has been demonstrated that it was possible to dissolve these basal insulins, of the type insulin glargine, the isoelectric point of which is between 5.8 and 8.5, at neutral pH, while maintaining a difference in solubility between the in-vitro medium (the container) and the in-vivo medium (under the skin), regardless of pH.

Application WO 2013/104861 A1, in particular, describes compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least (a) a basal insulin of which the isoelectric point pi is between 5.8 and 8.5 and (b) a co-polyamino acid carrying carboxylate charges substituted by hydrophobic radicals.

These compositions of the prior art have the major drawback of not being sufficiently stable to meet the specifications applicable to pharmaceutical formulations.

There is therefore a need to find a solution which makes it possible to dissolve a basal insulin whose isoelectric point (pi) is between 5.8 and 8.5 while retaining its basal profile after injection but which also make it possible to satisfy at standard physical stability conditions for insuiine-based pharmaceuticals.

Surprisingly, the applicant has found that the copolyamino acids carrying carboxylate charges and hydrophobic radicals according to the invention make it possible to obtain compositions in the form of solutions which not only meet the requirements described in WO 2013/104861 A1 but which moreover are able to impart improved physical stability to said compositions without having to increase the amount of excipients used.

These performances, a priori never achieved, are worse when the basal insulin, the isoelectric point of which is between 5.8 and 8.5, is combined in the composition with a meal insulin and / or a gastrointestinal hormone.

[00030] Thus, surprisingly, the affinity of the co-polyamino acids according to the invention for insulin glargine has been increased in that it allows solubilization and stabilization of the insulin glargine solutions to be obtained. [Hy] / [basal insulin] ratio lower than that of the prior art; these results are moreover obtained without altering, or even improving, the propensity of insulin glargine to precipitate as demonstrated in the experimental part.

This improvement in affinity also makes it possible, within the framework of chronic treatments, to limit the level of exposure to said excipients.

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 verified 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) a basal insulin whose isoelectric point (pi) is between 5.8 and 8.5 and

b) a co-polyamino acid of formula I

Q [Hy] i [PLG] _k

Formula I

In which :

j> 1; k> 2 said co-polyamino acid of formula I carrying carboxylate charges and consisting of at least two chains of PLG glutamic or aspartic units linked together by a radical or spacer Q [- *]> (i> 3 with i = j + k) linear or branched at least trivalent consisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen atoms and oxygen and / or radicals carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions, said radical Q [- *]> carrying at least one hydrophobic monovalent radical —Hy;

- said radical or spacer Q [- *], being linked to at least two chains of glutamic or aspartic units PLG by an amide function and,

- Said radical or spacer Q [- *], being linked to at least one hydrophobic radical --Hy of formula X below defined by an amide function.

- Said amide functions linking said radical or spacer Q [- *] i to at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q ′ of the radical or spacer Q [- *] i either by a glutamic or aspartic unit.

- the amide function linking said radical or spacer Q [- *] i to, at least one hydrophobic radical —Hy of formula X results from the reaction between an amine function and an acid function carried either by the precursor Q 'of the radical or spacer Q [- *] i or by the precursor Hy 'of the hydrophobic radical —Hy.

The pH of the compositions according to the invention is between 6.0 and 8.0, preferably between 6.6 and 7.8 or even more preferably between 6.8 and 7.6. Said co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is soluble in aqueous solution at pH between 6 and 8, at a temperature of 25 ° C and at a concentration at least equal to 60 mg / ml.

The term "physically stable composition" means compositions which meet the criteria of visual inspection described in the European, American and international pharmacopoeia, that is to say compositions which are clear and which do not contain visible particles, but also colorless.

The term “aqueous injectable solution” is understood to mean water-based solutions which meet the conditions of the EP and US pharmacopoeias.

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 C-terminal part, 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 “soluble” is intended to make it possible to prepare a clear solution devoid of particles at a concentration of less than 60 mg / ml in distilled water at 25 ° C.

In one embodiment, the radical or spacer Q [- *]> (i> 3) is represented by a radical of formula II:

QL - *] ï = ([Q '] q) [~ * l ·

Formula II In which 1 <q <5

The radicals Q ′ being identical or different and chosen from the group consisting of the radicals of formulas III to VI below, to form

Q [- *] ϊ (i> 3) * --- F _a --- IchJ — F _a .--- * ¹ Formula III

In which 1 <t <8 ^{D 1 2} Formula IV

In which :

At least one of the ui or U2 is different from 0.

If ui * 0 then ui '* 0 and if U2 * 0 then U2' * 0, ui 'and U2' are identical or different and, <u <4, <ui '<4, <ui <4, <u ₂ '<4 <U2 <4 and,

Formula V

In which :

v, ν 'and v identical or different, v + v' + v <15

*

Formula VI

In which :

wi 'is different from 0, <w ₂ <1, wi <6 and wi'<6 and / or w ₂ <6 and w ₂ '<6 with Fx = Fa, Fb, Fc, Fd, Fa', Fb ' , Fc ', Fc and Fd' identical or different representing -NH- or -CO- functions and Fy representing a trivalent nitrogen atom -N =, two radicals Q 'being linked together by a covalent bond between a carbonyl function , Fx = -CO-, and an amine function Fx - -NH- or Fy = -N =, thus forming an amide bond, [00041] In one embodiment, if Fa and Fa 'are -NH-, then t > 2.

In one embodiment, if Fa and Fa 'are -CO-, then t> l.

In one embodiment, if Fa and Fa 'are -CO- and -NH-, then t> l.

In one embodiment, if Fb and Fb 'are -NH-, then u and ui'> 2 and / or u /> 2.

In one embodiment, if Fc, Fc 'and Fc are -NH- then at least two of v, v' and v are different from 0.

In one embodiment, if Fc, Fc 'and Fc are 2 -NH- and 1 -CO- then at least one of the indices of - (CH ₂ ) - carrying a nitrogen is different from 0.

In one embodiment, if Fc, Fc 'and Fc are 1 -NH- and 2 -CO- then no conditions.

In one embodiment, if Fc, Fc 'and Fc are -CO- then at least one of v, v' and v is different from 0.

In one embodiment, if Fd and Fd 'are -NH-, wl and wl'> 2 and / or w2 and w'2> 2.

In one embodiment, if Fd and Fd 'are -CO-, wl and wl'> 1 and / or w2 and w2 '> 1.

In one embodiment, if Fd and Fd 'are -CO- and -NH-, wl and wl'> 1 and / or w2 and w2 '> 1.

Hy and PLG being linked to Q [- *], by a Fx or Fy function by a covalent bond to form an amide bond with a -NH- or -CO- function of PLG or Hy.

In one embodiment, 1 <q <4.

In one embodiment, v + v '+ v <15.

In one embodiment, at least one of the Q 'is a radical of formula

III

III, the precursor of which is a diamine.

In one embodiment, the precursor of the radical of formula III is a diamine chosen from the group consisting of ethylene diamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5-diaminopentane , propylene diamine, pentylene diamine.

In one embodiment, the precursor of the radical of formula III is an amino acid.

In one embodiment, the precursor of the radical of formula III is an amino acid chosen from the group consisting of aminobutanoic acid, aminohexanoic acid and beta-alanine.

In one embodiment, the precursor of the radical of formula III is a diacid.

In one embodiment, the precursor of the radical of formula III is a diacid chosen from the group consisting of succinic acid, glutaric acid and adipic acid.

In one embodiment, at least one of the Q 'is a radical of formula

IV,

whose precursor is a diamine.

In one embodiment, the precursor of the radical of formula IV is a diamine chosen from the group consisting of diethylene glycol diamine, triethylene glycol diamine, l-amino-4,9-dioxa-12-dodecanamine and 1- amino4,7,10-trioxa-13-tridecanamine.

In one embodiment, at least one of the Q 'is a radical of formula

V

the precursor of which is chosen from the group consisting of amino acids.

In one embodiment, the precursor of the radical of formula V is an amino acid chosen from the group consisting of lysine, aspartic acid, glutamic acid, ornithine, acid 1,3- diaminopropionic.

In one embodiment, at least one of the Q 'is a radical of formula

group consisting of triacids.

the precursor is chosen from [00067] In one embodiment, the precursor of the radical of formula V is a triacid chosen from the group consisting of tricarballylic acid.

In one embodiment, at least one of the Q 'is a radical of formula

group made up of triamines.

the precursor is chosen from [00069] In one embodiment, the precursor of the radical of formula V is a triamine chosen from the group consisting of tris-2 (2-aminomethane) amine.

In one embodiment, at least one of the Q 'is a radical of formula

* whose precursor is a triamine.

In one embodiment, w ₂ = 0 and the precursor of the radical of formula VI is a triamine chosen from the group consisting of spermidine, norspermidine, and diethylenetriamine and bis (hexamethylene) triamine.

In one embodiment, w ₂ = 0 and the precursor of the radical of formula VI is spermidine.

In one embodiment, w ₂ = 0 and the precursor of the radical of formula VI is norspermidine.

In one embodiment, w ₂ = l and the precursor of the radical of formula VI is a tetramine.

In one embodiment, w ₂ = 1 and the precursor of the radical of formula VI is a tetramine chosen from the group consisting of spermine and triethylenetetramine.

In one embodiment, the PLGs are linked to Fx with Fx = -NH- or to Fy by at least one carbonyl function of the PLG.

In one embodiment, the PLGs are linked to Fx with Fx = -NH- or to Fy by at least one carbonyl function which is not in the C terminal position of the PLG.

In one embodiment, the PLGs are linked to Fx with Fx = -NH- or to Fy by the carbonyl function in the C terminal position of the PLG.

In one embodiment, the PLGs are linked to Fx with Fx = -NH- by the carbonyl function in the C terminal position of the PLG.

In one embodiment, the PLGs are linked to Fx with Fx = Fy by the carbonyl function in the C terminal position of the PLG.

In one embodiment, the Hy are linked to Fx with Fx = -NH- or to Fy by a carbonyl function of Hy carried by GpR, GpA, GpG, GpH, GpL or GpC.

In one embodiment, the Hy are linked to Fy by a carbonyl function of Hy carried by GpR, GpA, GpG, GpH, GpL or GpC.

In one embodiment, the Hy are linked to Fx with Fx = -NH- by a carbonyl function of Hy carried by GpR, GpA, GpG, GpH, GpL or GpC.

In one embodiment, the PLGs are linked to Fx, with Fx = -CO- by the nitrogen atom in the N-terminal position of the PLG.

In one embodiment, the Hy are linked to Fx with Fx = -CO- by a nitrogen atom of Hy carried by GpR, GpA, GpG, GpL or GpH.

In one embodiment the q Q ′ are chosen from the group comprising the radicals of formulas VI, III and IV and Q comprises a radical of formula VI with q> 1 and Q [- *] i is a radical in which i = 3 and said co-polyamino acid of formula I is a copolyamino acid of general formula

Q [Hy] j [PLG] k

With j = l and k = 2

Hy defined by formula X is linked to Q 'via a covalent bond to Fa, Fa', Fb, Fb ', Fd, Fd' or Fy thus forming an amide bond

- the 2 PLG chains being linked to Q 'via a covalent bond to Fa, Fa', Fb, Fb ', Fd, Fd' or Fy, thus forming an amide bond.

In one embodiment q = 1.

In one embodiment, Hy is linked to Q 'via a covalent bond between

Fy and a carbonyl function of Hy carried by GpR, GpA, GpG, GpH or GpL to form an amide bond.

In one embodiment, the PLGs are linked to Q 'via a covalent bond between Fd, Fd' (Fd and Fd '= -NH-) and the carbonyl function in the C terminal position of the PLG chain, thus forming an amide bond.

In one embodiment Q 'is a radical of formula VI.

In one embodiment, Q ′ is a radical of formula VI in which:

W2 = w2 = 0 and 3 <wi <4 and 3 <wi '<4.

In one embodiment, Q 'is a radical of formula VI in which W2 = w2 = 0 and wi = 3 and wi' = 4.

In one embodiment, Q 'is a radical of formula VI in which W2 = w2 = 0 and wi = wi' = 3.

In one embodiment Fd = Fd '= - NH- and are each independently linked by a covalent bond to a terminal carbonyl function of a PLG forming an amide bond and Fy is linked by a covalent bond to a carbonyl function hydrophobic Hy forming an amide bond.

In one embodiment the q Q ′ are chosen from the group comprising the radicals of formulas III, IV and V and Q comprises at least one radical of formula V with q> 1 and Q [- *] i is a radical in which i = 3 and said co-polyamino acid of formula I is a copolyamino acid of general formula

Q [Hy] j [PLG] k

With j = l and k = 2

- Hy being defined by the formula X, linked to Q 'via a covalent bond to Fc, Fc', Fc, Fb, Fb ', Fa or Fa' thus forming an amide bond

- the 2 PLG chains being linked to Q 'via a covalent bond with Fc, Fc', Fc, Fb, Fb ', Fa or Fa', thus forming an amide bond.

In one embodiment, Hy is linked to Q ′ via a covalent bond with a carbonyl function of Hy carried by GpR, GpG, GpA, GpH, GpL or GpC to form an amide bond.

In one embodiment, Hy is linked to Q ′ via a covalent bond with an amine function of Hy carried by GpR, GpG, GpA, GpL or GpH to form an amide bond.

In one embodiment, the PLG chains are linked to Q 'via a covalent bond between Fc, Fc, Fb, Fb', Fa or Fa 'and the carbonyl function in the C terminal position of the PLG chain, thus forming an amide bond.

In one embodiment, the PLG chains are linked to Q 'via a covalent bond between Fc, Fc, Fb, Fb', Fa or Fa 'and the amine function in the N-terminal position of the PLG chain, thus forming an amide bond.

In one embodiment, Q ′ is a radical of formula V and q = 1.

In one embodiment, Q ′ is a radical of formula V linked to one or two radicals of formula III and 2 <q <3.

In one embodiment, Q ′ is a radical of formula V linked to one or two radicals of formula IV and 2 <q <3.

In one embodiment, Q ′ is a radical of formula V linked to one or two radicals of formula III and q = 2.

In one embodiment the q Q 'are chosen from the group comprising the radicals of formulas III, IV or V and Q comprises at least two radicals of formula V, with 2 <q <4 and Q [- *] i is a radical in which i = 4 and said copolyamino acid of formula I is a copolyamino acid of general formula

QLHyHPLGJk

With j = 2 and k = 2, the 2 Hy being defined by the formula X, linked to Q 'via a covalent bond with Fa, Fb or Fc', forming an amide bond, the 2 PLG chains being linked to Q 'via a covalent bond with Fa, Fb or Fc, thus forming an amide bond.

In one embodiment, the 2 Hy being defined by formula X, linked to Q 'via a covalent bond with Fc', forming an amide bond, and the 2 PLG chains being linked to Q 'via a covalent bond with Fc, thus forming an amide bond.

In one embodiment, q = 2.

In one embodiment, q = 3 [000107] In one embodiment, q = 4.

In one embodiment, Fc is -CO- and Fa, Fa ', Fb and Fb' are -NH-.

In one embodiment, Fc 'is -NH- and Hy is linked to Fc' by the carbonyl function carried by GpR, GpG, GpA GpH or GpL from Hy.

In one embodiment, Fc is -NH- and PLG is linked to Fc by the carbonyl function in the C terminal position of the PLG.

In one embodiment Q is a radical formed from the radicals chosen from the radicals of formulas IV or V with at least two radicals of formula V, with 2 <q <3 and Q [-] i is a radical in which i = 4.

In one embodiment Q is a radical formed from the radicals chosen from the radicals of formulas III or V with at least two radicals of formula V, with <q <3 and Q [-] i is a radical in which i = 4.

In one embodiment Q is a radical formed from the radicals chosen from the radicals of formula V with at least two radicals of formula V, with 2 <q <

and Q [-] i is a radical of formula in which i = 4.

In one embodiment the q Q ′ are chosen from the group comprising the radicals of formulas Vi and III and Q comprises at least two radicals of formula VI, with 2 <q <3 and Q [- *] i is a radical in which i = 4 and said copolyamino acid of formula I is a copolyamino acid of general formula

Q [Hy] j [PLG] k

With j = 2 and k = 2

the 2 Hy being defined by formula X, linked to Q ′ via a covalent bond with Fy, forming an amide bond,

- the 2 PLG chains being linked to Q 'via a covalent bond with Fd or Fd', thus forming an amide bond.

In one embodiment the q Q 'are chosen from the group comprising the radicals of formulas VI and III and Q comprises at least two radicals of formula VI, with q = 3 and Q [- *] i is a radical where i = 4.

In one embodiment the q Q 'are chosen from the group of radicals of formulas III, IV, V or VI with at least two radicals chosen from the radicals of formula V and the radicals of formula VI, with 2 < q <5 and Q [-] i is a radical in which 4 <i <6 and said co-polyamino acid of formula I is a copolyamino acid of general formula

Q [Hy] j [PLG] _k

With j = let3 <k <5

Hy defined by formula X is linked to Q ′ via a covalent bond with Fa, Fb, Fc or Fy, forming an amide bond,

the k PLG chains being linked to Fa, Fa ', Fb, Fb', Fc, Fd or Fd 'by a covalent bond, thus forming an amide bond.

In one embodiment the q Q ′ are chosen from the group of radicals of formulas III, IV, V or VI with at least two radicals chosen from the radicals of formula V and the radicals of formula VI, with 2 <q <3 and Q [- *] i is a radical in which i = 4 and said co-polyamino acid of formula I is a copolyamino acid of general formula I:

Q [Hy] j [PLG] i <

Formula I

Withj = let k> 3

- Hy being defined by the formula X, linked to Q ′ via a covalent bond with Fc, forming an amide bond,

- the 3 PLG chains being linked to Fc, Fd, Fd 'by a covalent bond, thus forming an amide bond.

In one embodiment, Q is a radical formed from at least one radical of formula VI and at least one radical of formula V with q> 2 and Q [- *] i is a radical in which i = 4 [000118] In one embodiment, with] - 1 and k = 3

Fc 'with Fc' = -CO- is linked to Fy by covalent bond to form an amide bond Fc is linked to a PLG chain by covalent bond to form an amide bond.

In one embodiment, Fc is -NH- and is linked to the PLG by the carbonyl in the C-terminal position to form an amide bond.

In one embodiment, Fc is -NH- and is linked to the carbonyl of Hy carried by GpR, GpA, GpG, GpH, GpL or GpC.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X as defined below:

- ^ GpR ^ - ^ GpG ^ - (GpA) GpH) GpC

Formula X in which

GpR is chosen from the radicals of formulas VII, VU 'or VU:

”'Rormuie seen. or '* Form VII'or

OO * _1Lr_J1_ * _Formu | _eVir .

Identical or different GpG and GpH are chosen from the radicals of formulas

XI or XI ':

* - NH - G - NH - *

Formula XI Formula ΧΓ

GpA is chosen from radicals of formula VIII * NH A * - [NH 1 *

Formula VIII

Wherein A 'is selected from the radicals of formula VIII', VIII or HIV ^'A \ _^1/0 ° *

Formula VIII '

HIV formula

Formula VIII '

-GpL is chosen from the radicals of formula XII .ir

HN * Formula XII,

GpC is a radical of formula IX:

*

Formula IX;

- the * indicate the sites of attachment of the different groups linked by amide functions;

- a is an integer equal to 0 or 1 and a '= 1 if a = 0 and a' = 1, 2 or 3 if a = 1;

a 'is an integer equal to 1, 2 or 3 b is an integer equal to 0 or 1;

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

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

- e is an integer equal to 0 or 1;

- g is an integer equal to 0, 1, 2, 3 to 4 to 5 or 6;

- h is an integer equal to 0, 1, 2, 3 to 4 to 5 or 6;

I is an integer equal to 0 or 1 and Γ = 1 if I = 0 and I '= 2 if I = 1;

- r is an integer equal to 0 or 1, and

- s' is an integer equal to 0 or 1;

- A, Ai, Az and A3, which are identical or different, are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms;

- B is 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, in which x indicates the number of carbon atoms and:

When the hydrophobic radical -Hy carries 1 -GpC, then 9 <x <25,

When the hydrophobic radical -Hy carries 2 -GpC, then 9 <x <15,

When the hydrophobic radical -Hy carries 3 -GpC, then 7 <x <13,

When the hydrophobic radical -Hy carries 4 -GpC, then 7 <x <11,

When the hydrophobic radical -Hy carries at least 5 -GpC then, 6 <x <11,

- G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).

- H is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).,

- 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:

- The hydrophobic radical (s) -Hy of formula X being linked to Q:

o via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by Q thus forming an amide function resulting from the reaction of an amine function carried by the precursor of Q and an acid function carried by the precursor -Hy 'of the hydrophobic radical -Hy, and o via a covalent bond between a nitrogen atom of the hydrophobic radical -Hy and a carbonyl carried by Q, thus forming an amide function resulting from the reaction of an amine function of the precursor - Hy 'of the hydrophobic radical -Hy and an acid function carried by the precursor of the radical Q, the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <M <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 for the PLG chains is between 5 and 250;

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

In one embodiment, said at least one hydrophobic radical - Hy is chosen from the radicals of formula X in which = 0, of formula Xd as defined below

- ^ GpR) ^ GpG-J— (GpA) --- (GpHj ^ —- GpC ^a Formula Xd in which

- GpR is chosen from the radicals of formulas VII, VII 'or VU:

H H H H * N R N * Form VII or * R — N * Form VII'or

OO _Formu | _eVir .

GpG is chosen from the radicals of formula XI or ΧΓ:

O

HE

H

G — N * Formula XI * - NH - G - NH - *

Formula ΧΓ

GpA is chosen from the radicals of formula VIII in which s '= 1 represented by the formula Villa or of formula VIII in which and s' = 0 represented by the formula VUIb:

HN

AT

HN— * Villa Formula

O

HE

H

A _r N— *

VUIb formula

GpC is a radical of formula IX:

Formula IX;

- the * indicate the sites of attachment of the different groups linked by amide functions;

- a is an integer equal to 0 or 1 and a '= 1 if a = O and a' = 1 or a '= 2 or a' = 3 if a = 1;

- a 'is an integer equal to lou 2 and o if a' is equal to 1 then a is equal to 0 or to 1 and GpA is a radical of formula VUIb and, o if a 'is equal to 2 then a is equal at 1, and GpA is a radical of formula Villa;

- b is an integer equal to 0 or 1;

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

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

- e is an integer equal to 0 or 1;

- g is an integer equal to O, to 1, to 2, to 3 to 4 to 5 or to 6;

- h is an integer equal to O, 1, 2, 3 to 4 to 5 or 6;

r is an integer equal to 0 or 1, and

- s' is an integer equal to 0 or 1;

- Ai is a linear or branched alkyl radical comprising from 1 to 6 carbon atoms;

- B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;

- C _x is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:

When the hydrophobic radical -Hy carries 1 -GpC, then 9 <x <25, • When the hydrophobic radical -Hy carries 2 -GpC, then 9 <x <15,

When the hydrophobic radical -Hy carries 3 -GpC, then 7 <x <13, • When the hydrophobic radical -Hy carries 4 -GpC, then 7 <x <11, • When the hydrophobic radical -Hy carries at least 5 -GpC then, <x <11,

- G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),

- H is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),

- 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:

- The hydrophobic radical (s) Hy of formula X being linked to Q:

o via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by Q thus forming an amide function resulting from the reaction of an amine function carried by the precursor of Q and an acid function carried by the precursor of the radical hydrophobic, and o via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl carried by Q, thus forming an amide function resulting from the reaction of an amine function of the precursor -Hy 'of the hydrophobic radical and an acid function carried by the precursor of the radical Q.

the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <M <0.5;

when several hydrophobic radicals are carried by a co-polyamino acid then they are identical or different,

- the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;

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

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X as defined below in which I = 0,

GpA is chosen from the radicals of formula VIII in which s' = 1 and A 'chosen from the radicals of formula VIII or HIV' ,:

* - ^ GpR ^ -— ^ GpG ^ - (GpA) (GpH | - GpC ^has Formula Xd in which

GpR is chosen from the radicals of formulas VII, VU 'or VII:

H H Π H

NRN Form VII or * RN * Form VII 'or OO * _LLr_LL * _Formu | _{e vir} .

GpG is chosen from the radicals of formula XI or ΧΓ:

O

Il P dd *, * —NH — G — NH— *,,

G N Formula XI Formula XI

GpA is chosen from the radicals of formulas, City or VUId:

_z A ₁ -N _al H— *

U

I —Ν _β2

A3 Ν _α2 Η Formula VUId;

_/ A ₁ -N _a] H— * * —N | _sl

A ^ N _a2 H City Formula

GpC is a radical of formula IX:

Formula IX;

the * indicate the sites of attachment of the different groups linked by amide functions;

a is an integer equal to 0 or 1 and a '= 1 if a = 0 and a' = 2 if a = 1;

a 'is an integer equal to 2 or 3 and o if a' is equal to 1 then a is equal to 0 and, o if a 'is equal to 2 or 3 then a is equal to 1, and GpA is a radical of formula

City or VUId;

b is an integer equal to 0 or 1;

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

e is an integer equal to 0 or 1;

- g is an integer equal to 0, 1, 2, 3 to 4 to 5 or 6;

- h is an integer equal to 0, 1, 2, 3 to 4 to 5 or 6;

r is an integer equal to 0 or 1, and

- s' is an integer equal to 1;

- Al, A2, A3 identical or different are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms;

- B is 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, in which x indicates the number of carbon atoms and:

When the hydrophobic radical -Hy carries 1 -GpC, then 9 <x <25, • When the hydrophobic radical -Hy carries 2 -GpC, then 9 <x <15,

When the hydrophobic radical -Hy carries 3 -GpC, then 7 <x <13, • When the hydrophobic radical -Hy carries 4 -GpC, then 7 <x <11,

When the hydrophobic radical -Hy carries at least 5 -GpC then, <x <11,

The hydrophobic radical (s) Hy of formula X being linked to Q:

o via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by Q thus forming an amide function resulting from the reaction of an amine function carried by the precursor of Q and an acid function carried by the precursor -Hy 'of the hydrophobic radical, and o via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl carried by Q, thus forming an amide function resulting from the reaction of an amine function of the precursor -Hy' of the hydrophobic radical and an acid function carried by the precursor of the radical Q.

- G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),

- H is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),

- 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:

the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <M <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 for the PLG chains is between 5 and 250;

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

In one embodiment, r = 0 and the hydrophobic radical of formula X is linked to Q via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by Q thus forming an amide function derived from the reaction of an amine function carried by the Q precursor and an acid function carried by the -Hy 'precursor of the hydrophobic radical.

In one embodiment, r = l and the hydrophobic radical of formula X is linked to Q:

via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl carried by Q, thus forming an amide function resulting from the reaction of an amine function of the precursor -Hy 'of the hydrophobic radical and an acid function carried by the precursor of the radical Q or, via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by Q, thus forming an amide function resulting from the reaction of an acid function of the precursor -Hy 'of the hydrophobic radical -Hy and an amine function of the precursor Q 'of the radical Q.

In one embodiment, 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 VII of 2 to 12 carbon atoms or if GpR is a radical of formula VII 'of 1 to 11 carbon atoms;

o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula VII of 2 to 11 carbon atoms or if GpR is a radical of formula VII 'of 1 to 11 carbon atoms, said alkyl radical carrying one or several functions -CONH2, and o an ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

In one embodiment, if GpA is a radical of formula Ville and r = l, then:

the GpCs are linked to Nai and N "2 and Q is linked via GpR to Npi, or

Its GpCs are linked to N _o i and N _P i, and Q is linked via GpR to N "₂; or the GpCs are linked to N _a2 and Npi, and Q is linked via GpR to N "i.

[000128] In one embodiment, if GpA is a radical of formuSe Ville and r = 0, then:

the GpCs are linked to N "i and N _a2 and Q is linked to N _p) ; or the GpCs are linked to N "i and N _P i, and Q is linked to N"₂; where the GpCs are linked to N _a2 and N _P i, and Q is linked to Nai.

In one embodiment, if GpA is a radical of formula VlIId and r = l, then the GpC are linked to N "i, and N _P i and Q is linked via GpR to N _p2 ; or the GpC are linked to N "i, N" ₂ and N _p2 and Q is linked via GpR to N _P i; or the GpCs are linked to N "i, N _P t and N _p2 and Q is linked via GpR to N _a2 ; or the GpCs are linked to N _a2 , N _P i and N _p2 and Q is linked via GpR to N "i.

In one embodiment, if GpA is a radical of formula VlIId and r = 0, then the GpCs are linked to N "i, N" ₂ and N _P i and Q is linked to N _p2 ; or the GpCs are linked to N _senior , N "2 and N _p2 and Q is linked to N _P i; or GpC are linked to Nai, N _P i and N _p2 and Q is linked to N"₂; or

- The GpCs are linked to N " ₂ , N _P i and N _p2 and Q is linked to Nai. The term" alkyl radical "means a carbon chain, linear or branched, which does not include a heteroatom.

[000132] 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 various elements represented.

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

In one embodiment, when a '= 1, x is between 11 and 25 (11 <x <25). In particular, when x is between 15 and 16 (x - 15 or 16) then r = 1 and R is an ether or polyether radical and when x is greater than 17 (x> 17) then r = 1 and R is a ether or polyether radical.

In one embodiment, when a '= 2, x is between 9 and 15 (9 <x <15).

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X in which a = 1 and a '= 1 of formula Xa as defined below:

h

1 '

Formula Xa in which GpA is a radical of formula VIII and A 'is chosen from the radicals of formula HIV' with s' = 0 and GpA is a radical of formula Formula VUIb

A.-N_ * ^{M1 N} Formula VUIb

And GpR, GpG, GpA, GpL, GpH, GpC, r, g, h, I and Γ 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 a = 1 of formula Xb as defined below:

^a Formula Xb in which GpA is a radical of formula VIII and A 'is chosen from the radicals of formula VIII' with s' = 1 and GpA is a radical of formula Formula Villa

HN * Villa Formula

And GpR, GpG, GpA, GpL, GpH, GpC, Ai, a ', r, g, h, I and 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 a = 1 as defined below:

^ GpH) - GpC ^a Formula Xb in which GpA is a radical of formula VIII and A is chosen from the radicals of formula VIII with s' = l and GpA is a radical of formula City Formula ^ -Ν ^ Η— *

A ₂ —Ν _α2 Η— *

City Package

And GpR, GpG, GpA, GpL, GpH, GpC, Ai, A ₂ , r, g, h, a ', I and Γ 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 a = 1 as defined below:

* - ^ GpR ^ - ^ GpG ^ —GpA - (GpLj— (GpH) GpC ^{r 9 1} L ^h Jl'Ja ·

Formula Xb in which GpA is a radical of formula VIII and A is chosen from the radicals of formula HIV 'with s' = l, and GpA is a radical of formula VUId _z Af-N _al H— * * —N _{r> l}

I

--- N | t2 \ -N _a2 H— *

VUId formula;

And GpR, GpG, GpA, GpL, GpH, GpC, Ai, A2, A3, a ', r, g, h, I and Γ 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 = l of formula Xc, as defined below:

^a 'Formula Xc in which GpR is a radical of formula VII.

H H * N — R — N * Form VII

And GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I, a' and Γ have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula Xc as defined below:

GpC ^has Formula Xc in which GpR is a radical of formula VH '.

R N * Formula VU '[000143] In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula Xc as defined below:

I * ^a Formula Xc in which GpR is a radical of formula VU.

OO * _LLr_11_ * _Format | _{e VII} „[000144] In one embodiment, said at least one hydrophobic radical --Hy is chosen from the radicals of formula X as defined below:

* - ^ GpR ^ - (GpG ^ - (GpÀ) (θρΕ) - (θρΗ) GpC

^a Formula X in which GpC is a radical of formula IX in which e = 0 and GpC is a radical of formula IXa 'x

Formula IXa [000145] In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X as defined below:

* - ^ GpR ^ - (GpG ^ - (GpÂ) (GpL) - (θρΗ) GpC

1 ' ^a ' Formula X in which GpC is a radical of formula IX in which e = l, b = 0 and GpC is a radical of formula IXd

O

Formula IXd [000146] In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X as defined below:

^a Formula X in which GpC is a radical of formula IX in! which e = l and GpC is a radical of formula IXb

Formula IXb In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xd as defined above. below:

GpG Formula IXd.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xd as defined below:

GpC Formula Xd in which GpC is a radical of formula IX in which e = 0, b = 0 and GpC is a radical of formula IXe

IXe [000149] In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula X in which GpA is a radical of formula VUIb, a '= 1 and I = 0 represented by the following formula Xe:

“( ^G P ^R ) - (GpG} - (GpA ^ - ^ GpH) - ^ - GpC

Formula Xe

GpR, GpG, GpA, GpH, GpC, r, g, h, and a have the definitions given above.

In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula X in which, a '= 2 and a = 1 and I = 0 represented by the following formula Xf:

h ² Formula Xf

GpR, GpG, GpA, GpH, GpC, r, g and h have the definitions given above.

In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula X in which h = 0.1 = 0 and Γ = 1 represented by the formula Xg next :

* - ^ GpR} - ^ GpG} - ^ - GpAj— | Gpc] ^r 9 aap _ormu | _e xg

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

In one embodiment, the composition according to the invention is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula X in which h = 0, a '= 1 represented by the following formula Xh:

^b Formula Xh

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

In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals are chosen from the hydrophobic radicals of formula X in which h = 0, a '= 2 and a = 1 represented by the formula Xi next:

* - ^ GpR ^ - ^ GpG ^ - GpA - (GpC) ₂ ^r Formula Xi

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

In one embodiment, the composition according to the invention is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula X in which h = 0 and g = 0, represented by the following formula Xj:

* - ^ GpR ^ -GpAj— [Gpc] ^raa formula ^Xj

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

In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula X in which h = 0 and g = 0 and a '= 1, represented by the following formula Xk:

'- (GpR (- (GpA (- GpC ^ra formula Xk

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

In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals of formula X are chosen from hydrophobic radicals of formula X in which h = 0 and g = 0 and a = 1 and a '= 2, represented by the following formula XI:

- (GpR 'j — GpA — ί Gpc) ^{r 2} Formula XI in which GpR, GpA, GpC and r have the definitions given above.

In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals of formula X are chosen from hydrophobic radicals of formula X in which a = 1 and a '= 1 and g = I = 0

represented by the following formula Xn:

GpR ^ --- GpA --- (GpHj-j-— GpC ^r Formula Xn [000158] In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals of formula X are chosen from radicals hydrophobes of formula X in which a = 1 and a '= 2 and g = I = 0, represented by the following formula Xp:

GpC ² Formula Xp [000159] In one embodiment, the composition according to the invention is characterized in that said hydrophobic radicals of formula X are chosen from hydrophobic radicals of formula X in which a = 1, g, h and I = 0 and a '- 3, represented by the following formula Xm:

* - ^ GpR) —GpA— (GpC) ^{r 3} Formula Xm in which GpA is a radical chosen from the radicals of formula VUId and GpR, GpC, r have the definitions given above.

In one embodiment, a = 0, [000161] In one embodiment h = 1 and g = 0, [000162] In one embodiment h = 0 and g = l, [000163] embodiment the q Q ′ are chosen from the group comprising the radicals of formulas VI, III and IV and Q comprises at least one radical of formula VI with q> 1 and Q [- *] i is a radical in which i = 3 and said co-polyamino acid of formula I is a copolyamino acid of general formula

Q [Hy] j [PLG] k

With j = l and k = 2 [000164] In one embodiment, r = 0, g = l and h = 0.

In one embodiment, r = l and GpR is chosen from the radicals of formula VU 'or VII and h = 0.

In one embodiment, r = l, g = 0 and GpR is a radical of formula VII 'and h = 0.

In one embodiment, r = l, g = 0 and GpR is a radical of formula VII ′ and h = 1.

In one embodiment, r = l, g = 0, GpR is a radical of formula VU ', GpA is chosen from the radicals of formula Villa or VUIb and h = 0.

In one embodiment, r = l, g = 0, GpR is a radical of formula VII ', GpA is chosen from the radicals of formula Villa or VUIb and h = 1.

In one embodiment, r = l, g = O, GpR is a radical of formula VU ', GpA is a radical of formula Villa and h = 0.

In one embodiment, r = l, g = 0, GpR is a radical of formula VII ', GpA is a radical of formula Villa and h = 1.

In one embodiment, r = l, g = 0, GpR is a radical of formula VII ', GpA is a radical of formula VUIb and h = 0.

In one embodiment, r = l, g = 0, GpR is a radical of formula VU ', GpA is a radical of formula VUIb and h = 1.

In one embodiment, r = 0, and GpA is chosen from the radicals of formula Villa and VUIb.

In one embodiment, r = 0, g = 0 and GpA is chosen from the radicals of formula Villa and VUIb.

In one embodiment, r = 0, GpA is chosen from the radicals of formula Villa and VUIb and h = 0 [000177] In one embodiment the q Q 'are chosen from the group comprising the radicals of formulas III, IV and V and Q comprises at least one radical of formula V with q> 1 and Q [- *] i is a radical in which i = 3 and said co-polyamino acid of formula I is a copolyamino acid of general formula

Q [Hy] j [PLG] k

With j = l and k = 2 In one embodiment the q Q ′ are chosen from the group comprising the radicals of formulas III, IV or V and Q comprises at least two radicals of formula V, with 2 <q <3 and Q [- *] i is a radical in which i = 4 and said polyamino acid co34 of formula I is a copolyamino acid of general formula I:

QEHyJjiPLGJk

With j = 2 and k = 2 In one embodiment the q Q 'are chosen from the group of radicals of formulas III, IV, V or VI with at least one radical of formula V and at least one radical of formula VI, with 2 <q <3 and Q [- *] i is a radical in which 4 <i <6 and said co-polyamino acid of formula I is a copolyamino acid of general formula I:

Q [Hy] j [PLG] k

With j = 1 and 3 <k <5 [000180] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xc, Xe, Xg, Xh Xj or Xk where r is 1 (r = l) and a is 0 (a = 0).

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xc, Xe, Xg, Xh Xj or Xk in which r is equal to 0 (r = 0) and a is equal to 0 (a = 0).

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r is equal to 1 (r = l) and a is equal to 1 (a = l).

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xa, Xe, Xh, Xk or XI, in which r = l and GpR is a radical of formula VII.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xf, Xi or XI in which r = l and GpR is a radical of formula VII.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which r = l and GpR is a radical of formula VII.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII in which R is a divalent alkyl radical comprising from 2 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 X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII in which R is a divalent linear alkyl radical comprising from 2 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 X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII in which R is a divalent alkyl radical comprising 2 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII '. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VU 'in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII 'in which R is a divalent alkyl radical comprising from 1 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 X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII or VU ', 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 according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII ′ or VII, 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 according to the invention is, characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII, VII ′ or VII in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII, VU 'or VII, in which R is a linear ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 atoms oxygen.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII, VIT or VU, in which R is an ether radical.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI which r = 1 and GpR is a radical of formula VII, VU 'or VII, 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 X, Xa, Xb, Xc,

Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = l and GpR is a radical of formula VII, VU 'or VU in which R is an ether radical represented by the formula

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII, VU 'or VU, in which R is a polyether radical.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII, VU ′ or VII, 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 according to the invention is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical of formula VII, VII 'or VH, in which R is a polyether radical chosen from the group consisting of radicals

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which r = 1 and GpR is a radical, in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which g = 1 and GpG is chosen from the radicals of formulas XIXa, XlXb, XIXc, XlXd, XIXe or XlXf below represented.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk or XI in which h = 1 and GpH is chosen from the radicals 10 of formulas XIXa, XlXb, XIXc, XlXd, XIXe or XlXf below represented.

O O .Apjy ; OC) 'NH ^{, Z} XlXb O _Η0 Α ^ γ · / NH ° * XIXc 0 i NH Q XlXd

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xj or Xk in which a is equal to 1 (a = 1) and a '= l, the radical GpA is a radical of formula VUIb and Ai is chosen from the group consisting of

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg,

Xf, Xi, Xj or XI in which the GpA radical of formula Villa is chosen from the group consisting of the radicals of formulas VUIaa and VlIIab below represented:

O HN \ * Formula VUIaa 0 HN : *: Formula VlIIab

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj or XI in which the GpA radical of formula Villa is a radical of formula

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj or XI in which the GpA radical of formula Ville is chosen from the group consisting of radicals in which Ai and A2, which are identical or different, are chosen from linear alkyl radicals.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj or XI in which the GpA radical of formula Ville is chosen from the group consisting of radicals in which Ai and A2, identical or different, are chosen from linear alkyl radicals comprising from 3 to 4 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj or XI in which the GpA radical of formula Ville is chosen from the group consisting of radicals in which Ai and A ₂ is chosen from linear alkyl radicals comprising 3 carbon atoms and A2 is chosen from linear alkyl radicals comprising 4 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj or XI in which the GpA radical of formula Ville is chosen from the group consisting of radicals in which Ai and A2, which are identical, are chosen from linear alkyl radicals comprising 3 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj or Xi in which the GpA radical of formula Ville is chosen from the group consisting of the radicals VlIIca and VlIIcb:

* -Ni Does *! NOT NH * VlIIca * -Nl-r The 'NH' VUIcb *

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, 5 Xf, Xi, Xj or XI in which the radical GpA of City formula is a radical of formula

VlIIca.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, 10 Xf, Xi, Xj or XI in which the radical GpA of City formula is a radical of formula

VlIIcb.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, 15 Xf, Xi, Xj or XI in which the radical precursor GpA of City formula is chosen

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg,

Xf, Xi, Xj or XI in which the precursor of the GpA radical of formula Ville is spermidine.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj or XI in which the precursor of the GpA radical City formula is norspermidine ._____________________________________________ norspermidine

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the GpA radical is chosen from the group of radicals of formula VUId in which Ai, A2 and A3, identical or different, are chosen from linear alkyl radicals comprising from 3 to 4 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the GpA radical of formula ΙΙΓ is chosen from the group the group of radicals of formula VUId in which Ai, and A3 identical are chosen from linear alkyl radicals comprising 3 carbon atoms and A2 is chosen from linear alkyl radicals comprising 4 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the GpA radical of formula VUId is a radical of formula VUIda:

[000225] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the precursor of the GpA radical of formula VUId is spermine:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, XI or Xm in which the GpC radical of formula IX is chosen from the group consisting of the radicals of formulas IXa, IXb or IXe below represented:

r V A iu A LA A ^h LA Vr Formula IXa A La a ^h L zCx ΓΤ ⁸ br AA o Formula IXb aav Formula IX

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, XI or Xm in which the radical GpC is of formula IXa. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, XI or Xm in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXa, IXb or IXe in which b is equal to 0, corresponding respectively to formulas IXd, IXe, and IXf below represented:

O 0 Formula IX λ ^ c _x 0 o Formula IXf i ^ Cx

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, XI or Xm in which the radical GpC corresponds to the formula IX or IXa in which b = 0, and corresponds to the formula IXd.

[000230] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, XI or Xm in which the GpC radical of formula IX 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 ci below: __________________________________________________

* * ch ₃ ch ₃ * * Y * * * * ch ₃ * y * γ * * h ₃ ct HgCl CHs

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, XI or Xm in which the radical GpC of formula corresponds to formula IX or IXa 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

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk in which a '= l or Γ = 1 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear akyl radicals comprising from 11 to 25 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk in which a '= l or l = 1 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising from 11 to 25 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk in which a '= l or l = 1 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between it and 14 carbon atoms. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xe, Xg, Xh, Xj, Xk in which a '= l or l' = l in which the radical GpC of formula

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

x = ll x = 13 [000236] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk in which a '= l or l' in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xe, Xg, Xh, Xj, Xk in which a '= l or Γ = 1 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xe, Xg, Xh, Xj, Xk in which a '= l or Γ = 1 in which the radical GpC of formula IX is chosen from Se group consisting of the radicals in which Cx is chosen in the formulas below:

made up of

x = 16 *

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xe, Xg, Xh, Xj, Xk in which a '= l or l' = l in which the GpC radical of formula IX 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 according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xe, Xg, Xh, Xj, Xk in which a '= l or Γ = 1 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk in which a '= l or l = l in which the GpC radical of formula IX 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:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk in which a '= l or l = 1 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 19 and 25 carbon atoms. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xe, Xg, Xh, Xj, Xk in which a '= l or l' = l in which the radical GpC of formula

IX 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 = 21 [000244] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk in which a '= l or l = l in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 19 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI in which a '= 2 or Γ = 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising between 9 and 15 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI in which a '= 2 or l '= 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising between 9 and 15 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI in which a '= 2 or Γ = 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising 9 or 10 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI in which a '= 2 or l '= 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI in which a '= 2 or Γ-2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 11 and 15 carbon atoms. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xf, Xg, Xi, Xj, XI in which a '= 2 or l' = 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 11 and 13 carbon atoms. In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,

Xf, Xg, Xi, Xj, XI in which a '= 2 or l' = 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen in the formulas below:

radical group

x = 11 * λ x = 13

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI in which a '= 2 or l '= 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising 14 or 15 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI in which a '= 2 or l '= 2 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xg, Xj, Xm in which a '= 3 in the island the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising between 7 and 13 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xg, Xj, Xm in which a '= 3 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising between 7 and 13 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, ^x 9, Xj, Xm in which a '= 3 in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising 7, 9 or 11 carbon atoms.

In the formulas, the * indicate the sites of attachment of the hydrophobic radicals to at Q [- *] i. The Hy radicals are attached to Q [- *], via amide functions.

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

- to Q [- *] i and

- at GpG if g = 1 or at GpA if g = 0.

In the Villa, VUIb, Ville and VUId formulas, the * indicates, from left to right respectively, the GpA attachment sites:

- at GpG if g = 1 or at GpR if r = 1 and g = 0 or at Q [- *], if g = r = 0 and

- to GpL if I = 1 or to GpH if h = l and 1 = 0 or to GpC if I = h = 0 [000260] In formula IX, the * indicates the site of attachment of GpC:

- at GpH if h = 1,

- at GpL if I = 1 and h = 0

- at GpA sia = leth = l = 0

- at GpG sig = leth = l = a = O

- at GpR sir = leth = l = a = g = O

- at Q [- *] i sih = l = a = g = r = 0

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

The Hy, GpR, GpG, GpA, GpL and GpC radicals are each independently identical or different from one residue to another.

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula

• D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • X represents a cationic entity chosen from the group comprising the alkaline cations, • Ra and Ra ', identical or different, are a radical chosen from the group consisting of an H, a linear acyl group at C2 to CIO, a branched acyl group at C3 to CIO, a benzyl, a terminal "amino acid" unit and a pyroglutamate, • Q , Hy and j have the meanings given above.

• 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 at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R _a and R _a ', identical or different, are chosen from the group consisting of an H and a pyroglutamate.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula

XXXa 'following:

In which :

• D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • X represents a cationic entity chosen from the group comprising the alkaline cations, • Q, Hy and j have the meanings given above.

• R _a and R _a ', identical or different, are a radical chosen from the group consisting of an H, a linear acyl group from C2 to CIO, a branched acyl group from C3 to CIO, a benzyl, an “amino acid” unit »Terminal and a pyroglutamate, • ni + mi represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid carrying a radical -Hy, • n2 + m2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid not carrying a -Hy radical, • m + n2 = n and mi + rm = m • n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number d 'monomeric units per copolyamino acid chain 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 at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula

Next XXXa:

In which :

• D represents, independently, either a group -CH ₂ - (aspartic unit) or a group -CH ₂ -CH ₂ - (glutamic unit), • Ri represents a radical or spacer of formula Q [- *] <as previously defined, • X represents a cationic entity chosen from the group comprising the alkaline cations, • Q, Hy and j have the meanings given above.

• R _a and R _a ', identical or different, are at least one hydrophobic radical Hy and a radical chosen from the group consisting of -Hy, an H, a linear acyl group at C2 to CIO, a branched acyl group at C3 to CIO, a benzyl, a terminal "amino acid" unit and a pyroglutamate, • 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 at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula

in which, • D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • R.2 represents a radical or spacer of formula Q [- *], such as previously defined, • X represents a cationic entity chosen from the group comprising the alkaline cations, • Rb and Rb ', identical or different, are a radical -NR'R, R' and R identical or different being chosen from the group consisting with H, linear or branched or cyclic C2 to CIO alkyls, 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 group consisting of O, N and S;

• Q, Hy and j have the meanings given above.

• 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 at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula

XXXb 'following:

Formula XXXb 'in which:

• D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • R2 represents a radical or spacer of formula Q [- *] as defined above, "X represents a cationic entity chosen from the group comprising the alkaline cations, • Q, Hy and j have the meanings given above.

• Rb and Rb ', identical or different, are 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 CIO alkyls, 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 comprise heteroatoms, chosen from the group consisting of O, N and S;

• nl + ml represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid carrying a radical -Hy • n2 + m2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid of radical -Hy • nl + n2 = n and ml + m2 = m η + 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 co-polyamino 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 at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula

Next XXXb:

Form XXXb

In which :

• D represents, independently, either a group -CH ₂ - (aspartic unit) or a group -CH ₂ -CH ₂ - (glutamic unit), • R ₂ represents a radical or spacer of formula Q [- *] i such that previously defined, • X represents a cationic entity chosen from the group comprising the alkaline cations, • Rb and Rb ', identical or different, are at least one hydrophobic radical Hy and a radical chosen from the group consisting of a hydrophobic radical -Hy and 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 CIO alkyls, benzyl and said R' and R alkyls which can together form one or more saturated, unsaturated and / or aromatic and / or carbon rings which may contain heteroatoms, chosen from the group consisting of O, N and S;

• Q, Hy and j have the meanings given above.

• 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 when the co-polyamino acids comprises aspartate units, then the co-polyamino acids may also comprise monomeric units of formula VIII and / or HIV ′ :

Form XXXX

Called "co-polyamino acid with statistical grafting" a copolyamino acid carrying carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula XXXa and XXXb.

Called "co-polyamino acid with defined grafting" a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, a copolyamino acid of formula XXXa, XXXa ', XXXb and XXXb'.

In one embodiment, the composition according to the invention is characterized in that Ri is a radical chosen from the group consisting of 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.

In one embodiment, the composition according to the invention is characterized in that Ri is a radical chosen from the group consisting of a linear acyl group in C2 to Cio or a branched acyl group in C3 to Cio.

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 XXXa, XXXa ', XXXb or XXXb' in which the co-polyamino acid is chosen from copolyamino acids in which the group D is a group -CH2- (aspartic unit).

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 XXXa, XXXa ', XXXb or XXXb' in which the co-polyamino acid is chosen from copolyamino acids in which the group D is a group -CH2-CH2- (glutamic unit).

The hydrophobic radical ratio by basal insulin is defined as the ratio of their respective molar concentrations: [Hy] / [basal insulin] (mol / mol) to obtain the expected performance, namely the solubilization of insulin basal at pH between 6.0 and 8.0, precipitation of basal insulin and stability of the compositions according to the invention.

The minimum value of the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin], measured is the value at which the basal insulin is solubilized, because solubilization is the minimum effect to be obtained; this solubilization conditions all the other technical effects which can only be observed if the basal insulin is solubilized at pH between 6.0 and 8.0.

In the compositions according to the invention, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] can be greater than the minimum value determined by the solubilization limit.

In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <2.

In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <1.75.

[000282] In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <1.5.

In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <1.25.

In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <1.00.

In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <0.75.

[000286] In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <0.5.

In one embodiment, the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] <0.25.

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

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

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

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 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 lies in a method for preparing stable injectable compositions.

In one embodiment, the invention also relates to the precursors of said hydrophobic radicals of formula X.

In one embodiment, the invention also relates to the copolyamino acid of formula I

Q [Hy] j [PLG] _k

Formula I

In which :

j> 1; k> 2

said co-polyamino acid of formula I carrying carboxylate charges and consisting of at least two chains of glutamic or aspartic PLG units linked together by a radical or spacer Q [- *] i (i> 3 with i = j + k) linear or branched at least trivalent consisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and / or carrying one or more heteroatoms consisting of nitrogen atoms and d oxygen and / or radicals carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions, said radical Q [- *], carrying at least one hydrophobic monovalent radical --Hy;

- said radical or spacer Q [- *], being linked to at least two chains of glutamic or aspartic units PLG by an amide function and,

- Said radical or spacer Q [- *] being linked to at least one hydrophobic radical —Hy of formula X below defined by an amide function.

- Said amide functions linking said radical or spacer Q [- *], to at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q ′ of the radical or spacer Q [- *] “either by a glutamic or aspartic unit.

- The amide function linking said radical or spacer Q [- *] <to, at least one hydrophobic radical —Hy of formula X results from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] î either by the precursor Hy 'of the hydrophobic radical —Hy,

- The radical -Hy being defined above,

- The radical or spacer Q [- *] î being defined above.

In one embodiment, the invention also relates to the compound of formula Ib precursor of the co-polyamino acid of formula I defined above:

Q '[Hy] j

Formula Ib

In which :

d> 1

said compound of formula Ib consisting of the precursor of the radical or spacer Q ′ [- *] j linear or branched consisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and / or carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or radicals carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions, said radical

Q '[- *] j carrying at least one monovalent hydrophobic radical —Hy linked by amide bonds, and

- the precursor of the radical or spacer Q ′ [- *] j carrying at least k reactive amine or acid functional groups, free,

- Said amide functions linking said radical or spacer Q '[- *] to the at least hydrophobic radical -Hy resulting from the reaction between an amine function and an acid function respectively carried either by the precursor Q' of the radical or spacer Q ' [- *] j either by the precursor -Hy 'of the hydrophobic radical -Hy,

- Said radical or spacer Q '[- *] - j being chosen from the radicals of formula Q [~ *] j = ([Q'] q) [ ^- * Jj, in which 1 <q <5 • the radicals Q 'being identical or different and chosen from the group consisting of the radicals of formulas III to VI defined above, to form Q [- *] j (j> 3), whose functions Fx = Fa, Fb, Fc, Fd , Fa ', Fb', Fc ', Fc and Fd' identical or different representing functions -NH- or -CO- and Fy representing a trivalent nitrogen atom -N =, • two radicals Q 'being linked together by a covalent bond and a carbonyl function, Fx = -CO-, and an amine function Fx = -NH- or Fy - -N =, thus forming an amide bond, • and when the at least two reactive functions are not linked to a radical Q ′ or to a hydrophobic radical -Hy they constitute free carboxylic acid or amine functions.

In one embodiment, the invention also relates to the copolyamino acid of formula the precursor of the co-polyamino acid of formula I defined above:

Q [PLG] _k

Formulate the

In which :

k> 2

- Said co-polyamino acid of formula Ia carrying carboxylate charges and consisting of at least two chains of glutamic or aspartic PLG units linked together by the precursor of the radical or spacer Q [- *] k linear or branched consisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or radicals carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions,

- Said radical or spacer Q [- *] k being linked to at least two chains of glutamic or aspartic units PLG by an amide function and, bearing after bonding to at least two chains of glutamic or aspartic units PLG at least j functions amine or acid reagents, free,

- Said amide functions linking said radical or spacer Q [- *] kaux at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] k either by a glutamic or aspartic unit,

- Said radical or spacer Q [- *] k being chosen from the radicals of formula Q [- *] _k = ([Q '] q) [- *] k, in which 1 <q <5 "the radicals Q' being identical or different and chosen from the group consisting of the radicals of formulas III to VI defined above, to form Q [- *] k (k> 3), whose functions Fx - Fa, Fb, Fc, Fd, Fa ', Fb', Fc ', Fc and Fd' identical or different representing functions -NH- or -CO- and Fy representing a trivalent nitrogen atom -N =, • two radicals Q 'being linked together by a covalent bond between a carbonyl function, Fx = -CO-, and an amine function Fx = -NH- or Fy = -N =, thus forming an amide bond, • and when the at least reactive function is not linked to a radical Q ′ or to at least two chains of glutamic or aspartic units they constitute free carboxylic acid or amine functions.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization.

In one embodiment, the composition according to the invention is characterized in that its PLG chains constituting the co-polyamino acid are obtained by ring-opening polymerization of a derivative of N-carboxyanhydride of glutamic acid or d 'a derivative of N-carboxyanhydride of aspartic acid.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are 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 PLG chains constituting the co-polyamino acid are obtained by polymerization of an N-carboxyanhydride derivative of glutamic acid.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of an N-carboxyanhydride derivative of glutamic acid chosen from the group consisting of poly (methyl glutamate N-carboxy anhydride (GluOMeNCA), poly (benzyl N-carboxy anhydride (GluOBzl-NCA) and polycarbyl t-butyl glutamate Ncarboxyanhydride (GluOtBu-NCA).

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

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

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using as 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 PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using as initiator ammonia or a primary amine 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 PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of 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 PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid, polymerization initiated by the amine functions carried by the radical or spacer Q [- *] i.

In one embodiment, the composition according to the invention is characterized in that its PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid chosen from the group consisting of poly (methyl glutamate N-carboxyanhydride (GluOMeNCA), benzyl Ν-carboxyanhydride poly (benzyl glutamate) (GluOBzl-NCA) and polycarbonate t-butyl ncarboxyanhydride (GluOtBu-NCA), polymerization initiated by the amino functions carried by the radical or spacer Q [- *]>.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of N-carboxyanhydride poly-L-methyl glutamate (L-GluOMeNCA), polymerization initiated by the amine functions carried by the radical or spacer Q [- *] i [000317] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of the Benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzlNCA), polymerization initiated by the amine functions carried by the radical or spacer Q [- *] i.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid, polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] k [Hy] j.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of an N-carboxyanhydride derivative of glutamic acid chosen from the group consisting of poly (methyl glutamate) N-carboxyanhydride (GluOMeNCA), poly (benzyl) glutamate (GluOBzl-NCA) and polycarbon t-butyl glutamate Ncarboxyanhydride (GluOtBu-NCA), polymerization initiated by the amino functions carried by the precursor of the radical Q [~~ *] k [Hy] j.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of the N-carboxyanhydride poly-L-methyl glutamate (L-GluOMe

NCA), polymerization initiated by the amine functions carried by the precursor of the radical QE- ^ MHyJj.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of the benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzlNCA), polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] k [Hy] j.

In one embodiment, the composition according to the invention is characterized in that the process for synthesizing the PLG chains constituting the copolyamino acid including the polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid comprises a step of hydrolysis of ester functions.

In one embodiment, this step of hydrolysis of ester functions can 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 PLG chains constituting the co-polyamino acid come 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 PLG chains constituting the co-polyamino acid come 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 PLG chains constituting the co-polyamino acid come 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 PLG chains containing the co-polyamino acid come 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 PLG chains constituting the co-polyamino acid come from a polyamino acid obtained by depolymerization of a higher molecular weight polyamino acid chosen from the group consisting of sodium polyglutamate and sodium polyaspartate.

In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid come 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 PLG chains constituting the co-polyamino acid come 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 amide bonds present in the co-polyamino acid come from methods of forming amide bonds well known to those skilled in the art.

In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid come from methods of forming amide bonds used for peptide synthesis.

In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid come from methods of forming an amide bond described in patent FR 2,840,614 (Chan, YP; and al.).

In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] i and between the radical or spacer Q [- *] i and the hydrophobic radical -Hy are derived from methods of forming an amide bond well known to those skilled in the art.

In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] <and between the radical or spacer Q [- *] i and the hydrophobic radical -Hy are derived from amide bond formation processes used for peptide synthesis.

In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *], and between the radical or spacer Q [- *] i and the hydrophobic radical -Hy are derived from processes for forming an amide bond described in patent FR 2,840,614 (Chan, YP; et al.).

In the following, the units used are for insulins those recommended by the pharmacopoeias whose correspondences in mg / ml are given in the table below:

Insulin Pharmacopoeia EP 8.0 (2014) US Pharmacopoeia - USP38 (2015) aspart 1U = 0.0350 mg insulin aspart 1 USP = 0.0350 mg insulin aspart lispro 1U = 0.0347 ai insulin lispro 1 USP = 0.0347 mq insulin lispro human 1IU = 0.0347 mg of human insulin 1 USP = 0.0347 mg human insulin glargine 1U = 0.0364 mg of insulin qlarqine 1 USP = 0.0364 mg of insulin qlarqine swine 1IU = 0.0345 mg of porcine insulin 1 USP = 0.0345 mg porcine insulin Bovine 1IU = 0.0342 mg bovine insulin 1 USP = 0.0342 mg bovine insulin

[000340] The term “basal insulin”, the isoelectric point of which is between

5.8 and 8.5 an insulin insoluble at pH 7 and whose duration of action is between 8 and 24 hours or more in standard models of diabetes.

These basal insulins whose isoelectric point is between 5.8 and 8.5 are recombinant insulins whose primary structure has been modified mainly by the introduction of basic amino acids such as Arginine or Lysine. They are described for example in the following patents, patent applications or publications WO 2003/053339, WO 2004/096854, US 5,656,722 and US 6,100,376, the content of which is incorporated by reference.

In one embodiment, the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine. Insulin glargine is marketed under the brand Lantus® (100 U / ml) or Toujeo® (300 U / ml) by SANOFI.

In one embodiment, the basal insulin whose isoelectric point is between 5.8 and 8.5 is a biosimilar insulin glargine.

A biosimilar insulin glargine is in the process of being marketed under the brand Abasaglar® or Basaglar® by ELI LïLLY.

In one embodiment, the compositions according to the invention comprise between 40 and 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 40 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 100 U / ml (or approximately 3.6 mg / ml) of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 150 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 250 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the co-polyamino acid, ie copolyamino acid / basal insulin, is between 0, 2 and 8.

[000356] In one embodiment, the mass ratio is between 0.2 and 6.

In one embodiment, the mass ratio is between 0.2 and 5.

In one embodiment, the mass ratio is between 0.2 and 4.

[000359] In one embodiment, the mass ratio is between 0.2 and 3.

In one embodiment, the mass ratio is between 0.2 and 2.

In one embodiment, the mass ratio is between 0.2 and 1.

In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 60 mg / ml. 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 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 compositions according to the invention further comprise a mealtime insulin. Prandial insulins are soluble at pH 7.

[000369] By mealtime insulin is meant a so-called rapid or "regular" insulin. So-called rapid meal insulins are insulins which must meet the needs caused by the ingestion of proteins and carbohydrates during a meal, they must act in less than 30 minutes.

In one embodiment, the so-called "regular" mealtime insulin is human insulin.

In one embodiment, the mealtime insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.

Human insulin is for example marketed under the brands Humulin® (ELI LILLY) and Novolin® (NOVO NORDISK).

[000374] The so-called very fast prandial insulins are insulins which are obtained by recombination and whose primary structure has been modified to reduce their action time.

In one embodiment, the so-called very fast prandial insulins are chosen from the group comprising insulin lispro (Humalog®), insulin glulisine (Apidra®) and insulin aspart (NovoLog® ).

In one embodiment, the meal insulin is insulin lispro.

[000377] In one embodiment, the meal insulin is insulin glulisine.

In one embodiment, the meal insulin is aspart insulin.

In one embodiment, the compositions according to the invention comprise in total between 60 and 800 U / ml of insulin with a combination of mealtime insulin and basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise in total between 100 and 500 U / ml of insulin with a combination of mealtime insulin and basal insulin, the isoelectric point of which is between 5.8 and 8.5. In one embodiment, the compositions according to the invention comprise in total between 40 and 500 U / ml of insulin with a combination of prandial insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 800 U / ml of insulin with a combination of mealtime insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 700 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 600 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 500 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 400 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 300 U / ml of insulin with a combination of mealtime insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 266 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 200 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprise a total of 100 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

In one embodiment, the compositions according to the invention comprising a total of 40 U / ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8.5.

The proportions between the basal insulin whose isoelectric point is between 5.8 and 8.5 and the mealtime insulin are for example in percentage of 25/75, 30/70, 40/60, 50/50 , 60/40, 63/37, 70/30, 75/25, 80/20, 83/17, 90/10 for formulations as described above comprising from 60 to 800 U / mL. However, any other proportion can be carried out. 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 (Glucagon like peptide-1 receptor agonist) and GIP (Glucose-dependent insulinotropic peptide), Oxyntomodulin (a derivative of proglucagon ), peptide YY, amylin, 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 chosen from the group consisting of exenatide or Byetta® (ASTRA-ZENECA), liraglutide or Victoza® (NOVO NORDISK ), lixisenatide or Lyxumia® (SANOFI), albiglutide or Tanzeum® (GSK) or dulaglutide or Trulicity® (ELI LILLY & CO), their analogs or derivatives and their pharmaceutically acceptable salts.

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

[000395] In one embodiment, the gastrointestinal hormone is exenatide 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. 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" is used, 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.

[000403] 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 100 mg / ml_. 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 albiglutide, its analogs or derivatives and their pharmaceutically acceptable salts is between 5 to 100 mg / ml.

In one embodiment, the concentration of dulaglutide, its analogs or derivatives and their pharmaceutically acceptable salts is between 0.1 to 10 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 commercial solutions of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and commercial solutions of GLP-1 RA, analog or GLP-1 RA derivative in volume ratios in the range of 10/90 to 90/10.

[000412] In one embodiment, the composition according to the invention comprises a daily dose of basal insulin and a daily dose of gastrointestinal hormone.

In one embodiment, the compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, between 0.05 and 0.5 mg / ml of exenatide [000414] In one embodiment, the compositions according to the invention comprise between 40 U / ml and 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / mL of Iiraglutide.

In one embodiment, the compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.01 1 mg / mL lixisenatide.

In one embodiment, the compositions according to the invention comprise between 40 U / ml and 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and, from 5 to 100 mg / mL albiglutide.

In one embodiment, the compositions according to the invention comprise between 40 U / ml and 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and, from 0.1 10 mg / mL dulaglutide.

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.04 to 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 1 to 10 mg / mL of liraglutide.

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 5 to 100 mg / mL of albiglutide.

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.1 to 10 mg / mL dulaglutide.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.04 to 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 1 to 10 mg / mL of liraglutide.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 5 to 100 mg / mL of albiglutide.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.1 to 10 mg / mL dulaglutide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.04 to 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 1 to 10 mg / mL of liraglutide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 5 to 100 mg / mL of albiglutide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.1 to 10 mg / mL dulaglutide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.04 to 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 1 to 10 mg / mL of liraglutide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 5 to 100 mg / mL of albiglutide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and from 0.1 to 10 mg / mL of dulaglutide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.04 to 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 1 to 10 mg / mL of liraglutide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 5 to 100 mg / mL of albiglutide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.1 to 10 mg / mL dulaglutide.

In one embodiment, the compositions according to the invention comprise 100 U / ml (or approximately 3.6 mg / ml) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, 0.04 to 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise 100 U / ml (or approximately 3.6 mg / ml) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, 1 to 10 mg / mL of liraglutide.

In one embodiment, the compositions according to the invention comprise 100 U / ml (or approximately 3.6 mg / ml) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 100 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and, from 5 to 100 mg / mL of albiglutide.

In one embodiment, the compositions according to the invention comprise 100 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.1 to 10 mg / mL dulaglutide.

In one embodiment, the compositions according to the invention comprise 40 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.04 to 0.5 mg / mL of exenatide.

In one embodiment, the compositions according to the invention comprise 40 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.

In one embodiment, the compositions according to the invention comprise 40 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 40 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 5 to 100 mg / ml of albiglutide .

In one embodiment, the compositions according to the invention comprise 40 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.1 to 10 mg / mL of Dulaglutide.

In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration between 0 and 5000 μΜ. In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 4000 μΜ. In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration between 0 and 3000 μΜ. In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 2000 μΜ. In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 1000 μΜ. In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 50 and 600 μΜ. In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 100 and 500 μΜ.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 200 and 500 μΜ.

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, Tris (trishydroxymethylaminomethane) and sodium citrate.

In one embodiment, the buffer is sodium phosphate.

In one embodiment, the buffer is sodium citrate.

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 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 and polysorbate.

The compositions according to the invention can also comprise additives such as toning agents.

In one embodiment, the tonicity agents are chosen from the group consisting of glycerin, sodium chloride, mannitol and glycine.

The compositions according to the invention can also comprise all the excipients in accordance with the pharmacopoeias and compatible with the insulins 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. The transdermal, oral, nasal, vaginal, ocular, oral, pulmonary administration routes are also envisaged.

The invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5.

The invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin. The invention also relates to single-dose formulations at pH between 7.0 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a prandial insulin.

The invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above. The invention also relates to single-dose formulations at pH between 7.0 and

7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above.

The invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, such as defined above. The invention also relates to single-dose formulations at pH between 7.0 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, as defined above. .

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5.

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin.

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above.

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, such as defined above.

The invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5.

The invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin.

The invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above.

The invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, such as defined above.

In one embodiment, the single-dose formulations further comprise a co-polyamino acid as defined above.

In one embodiment, the formulations are in the form of an injectable solution.

In one embodiment, the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine.

In one embodiment, the meal insulin is human insulin.

In one embodiment, the insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.

In one embodiment, the meal insulin is chosen from the group comprising insulin lispro (Humalog®), insulin glulisine (Apidra®) and insulin aspart (NovoLog®).

In one embodiment, the meal insulin is insulin lispro.

In one embodiment, the meal insulin is insulin glulisine.

In one embodiment, the meal insulin is aspart insulin.

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.

In one embodiment, the gastrointestinal hormone is exenatide.

[000503] In one embodiment, the gastrointestinal hormone is liraglutide.

[000504] In one embodiment, the gastrointestinal hormone is ie lixisenatide. In one embodiment, the gastrointestinal hormone is albiglutide.

[000506] In one embodiment, the gastrointestinal hormone is ie dulaglutide. The solubilization at pH between 6.0 and 8.0 of the basal insulins whose isoelectric point is between 5.8 and 8.5, by the co-polyamino acids carrying carboxylate charges and at least one radical hydrophobic according to the invention, can be observed and controlled in a simple manner, with the naked eye, by virtue of a change in appearance of the solution.

The solubilization at pH between 6.6 and 7.8 of the basal insulins whose isoelectric point is between 5.8 and 8.5, by the co-polyamino acids carrying carboxylate charges and at least one radical hydrophobic according to the invention, can be observed and controlled in a simple manner, with the naked eye, by virtue of a change in appearance of the solution.

In addition, and just as importantly, the Applicant has been able to verify that a basal insulin whose isoelectric point is between 5.8 and 8.5, solubilized at pH between 6.0 and 8.0 in presence of a co-polyamino acid carrying carboxylate charges and of at least one hydrophobic radical according to the invention retains its slow insulin action, whether alone or in combination with a prandial insulin or a gastrointestinal hormone.

The Applicant has also been able to verify that a prandial insulin mixed at a pH of between 6.0 and 8.0 in the presence of a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention and a basal insulin whose isoelectric point is between 5.8 and 8.5, retains its rapid insulin action.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin whose isoelectric point is between 5.8 and 8.5, and d 'A co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin, the isoelectric point of which is between 5.8 and 8.5, a solution of prandial insulin, and of a co-polyamino 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 between 6 and 8.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin, the isoelectric point of which is between 5.8 and 8.5, a solution of GLP-1 RA, an analog or derivative of GLP-1 RA, and of a co-polyamino 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 between 6 and 8.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin, the isoelectric point of which is between 5.8 and 8.5, a solution of prandial insulin, of a solution of GLP-1 RA or of an analog or 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 between 6 and 8.

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

If necessary, the composition of the mixture is adjusted to excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween®) by adding concentrated solutions of these excipients within the mixture. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.

Figure 1 :

In Figure 1, the average curves of glycaemia are shown in percent deviations from the basal level ± standard error of the average after simultaneous and separate administrations of Humalog® (100 IU / mL, 0.17 IU / kg) and Lantus® (100 IU / mL, 0.50 U / kg) (solid circles) and of the composition CB3-10 (266 U / ml, 0.67 U / kg) (empty squares); the administrations having been carried out on the dog (n = 10), by subcutaneous injection.

Examples

The invention is described in more detail through the following examples without limitation.

£ article-A_- Synthesis of the hydrophobic radicals "au.spacer" [000517] The hydrophobic radicals linked to the spacer are shown in Table 1.

A2 NOT \ ^. NH ₂ . 2 HCl / NH ! kx _J θ13 ^ 27 I _Z NH • é y ^N ^ C ₁₃ H ₂₇ A3 ^ nh 0 ^ ^ nh ₂ Ci __! θ13 ^ 27 >! H at ^X N ^ C _u j θ13 ^ 27 A4 rv □ J 0 O ’^ NH / YV-Vy ^ 0 Λ _ο / \ / ^Ο Χ V ^ ". ² ” H _; .,VS" AT 5 H ^ L rV 0 / y ^ nh ^ ^N yo "X oX \ / \ Aæ ⁰ Cr

A6 NH ^y \ / ^O 'X ^Zx _o ^z X / .NH ^ O < h ₂ n ^ .1 „... · TO ¹ νηχ ^ Υ / χ ^ ° X ^ , NH O Q Y ^ \ i ¹ NA H / C ₁₃ H _a / N ^ / - ^: 27 ^th O A7 -'X. ^ NH .0 NH x- ' H;> N x / 'k; > x .NHo T O N H x- CK - ^NH .A ^ y ο Ύ o ^ γ ^χ \ ι Λ .. „ti ~~ J / / - N ^x Η ₂ γΟ ₁₃ \ \ H27 ^G 13 ^ ''' O: AT 8 zx ^ NH N H Y H4L ^ A <ΝηΛ X ^ ^Χ ^ Υ- ^χΛχ ΝΗ ₂ o V \ H ^ Cn * γ \ H ₂₇ c ₁₃ / ^N --y / O A9 Η ^ γΑ tX NH οΑχγχ _ΝΗ2 (X, NH »ΛΛ ^M 27 ^C U j ο Γ A H _î7 C _fi ] A10 ^ 2zÇ 13 The ^ '\ ^ - ^NH 2 _z Λ = ο O χ ^, Νχ ^ NH ₂ / NOT 0 Ί NH ₂ O CK, NH \ Z O I kA H 27 ^C 13 ξ /

Table 1: List of hydrophobic radicals linked to the spacer.

Example Al - Molecule Al

Molecule 1: Product obtained by coupling between lauric acid and L-proline [000518] To a solution of lauric acid (31.63 g, 157.9 mmol) in THF (1 L) at room temperature are added successively N, Ndicyclohexylcarbodiimide (DCC) (33.24 g, 161.1 mmol) and N-hydroxysuccinimide (NHS) (18.54 g, 161.1 mmol). After 18 h of stirring at room temperature, the medium is cooled to 0 ° C for 20 min and filtered through a frit. L-proline (20 g, 173.72 mmol), diisopropylethylamine (DÎPEA) (137.5 mL) and water (120 mL) are added to the filtrate. After 24 h of stirring at room temperature, the solvent is evaporated and the residue is diluted in water (500 ml). The aqueous phase is washed with ethyl acetate (2 x 500 mL), acidified to pH ~ 1 with a 1N aqueous HCl solution and then extracted with dichloromethane (3 x 300 mL). The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo.

Yield: 34.3 g (73%)

H NMR ^J (CDCl₃, ppm): 0.87 (3H); 1.26 (16H); 1.70 (2H); 1.90-2.10 (3H); 2.35 (2H); 2.49 (1H); 3.48 (1H); 3.56 (1H); 4.60 (1H).

LC / MS (ESI): 298.2; (calculated ([M + H] ⁺ ): 298.2).

Molecule 2: Product obtained by the reaction between molecule 1 and L-lysine [000519] By a process similar to that used for the preparation of molecule 1 applied to molecule 1 (33.72 g, 113.36 mmol) and with L-lysine (8.70 g, 59.51 mmol), a white solid of molecule 2 is obtained.

Yield: 26.2 g (66%)

NMR (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] +): 705.6).

Molecule 3: Product obtained by the reaction between spermidine and 2- (tertbutoxycarbonyloxyimino) -2-phenylacetonitrile (Boc-ON) [000520] To a solution of spermidine (4.07 g, 28.00 mmol) in THF ( 70 mL) is added triethylamine (TEA, 8.50 g, 84.01 mmol) and the reaction medium is cooled to 0 ° C. A solution of Boc-ON (13.66 g, 55.45 mmol) in Se THF (220 mL) is added dropwise for 6 h 30 min then the medium is stirred for 18 h at room temperature. The reaction medium is concentrated under reduced pressure, the residue is diluted with DCM (280 mL) and the organic phase is washed successively with a 1N aqueous sodium hydroxide solution (2 x 140 mL), water (140 mL) , a saturated aqueous solution of NaCl (140 mL), dried over MgSO4, filtered and concentrated under reduced pressure. A white solid of molecule 3 is obtained after solubilization of the residue in chloroform, concentration under reduced pressure and drying under vacuum.

Yield: 10.25 g (quantitative)

H NMR ^J (CDCl₃, ppm): 1.38 to 1.59 (23H); 1.61-1.70 (2H); 2.60 (2H); 2.66 (2H); 3.12 (2H); 3.20 (2H); 4.83 (1H); 5.17 (1H).

LC / MS (ESI): 346.3; (calculated ([M + H] ⁺ ): 346.3).

Molecule 4: Product obtained by coupling between molecule 2 and molecule 3 [000521] To a solution of molecule 2 (5.56 g, 7.89 mmol) in chloroform (110 mL) are successively added triethylamine (1 , 04 g, 10.26 mmol), 1-hydroxybenzotriazole (HOBt, 1.39 g, 10.26 mmol) and N- (3dimethylaminopropyl) -N'-ethylcarbodiimide (EDC, 1.97 g, 10.26 mmol). After 15 min, molecule 3 (3.00 g, 8.68 mmol) is added and the reaction medium is stirred for 18 h at room temperature. The organic phase is washed successively with a saturated aqueous NH4Cl solution (110 mL), a saturated aqueous solution of NaHCO3 (110 mL), a saturated aqueous solution of NaCl (110 mL), dried over MgSO4, filtered and concentrated under reduced pressure . A yellowish molecule oil is obtained after purification by chromatography on silica gel (eluent: DCM, methanol).

Yield: 6.20 g (78%)

^X H NMR (CDaOD, ppm): 0.90 (6H); 1.22-2.46 (78H); 2.96-3.31 (6H); 3.31-3.76 (8H); 4.29-4.55 (2H); 4.65-4.85 (1H).

Molecule Al [000522] To a solution of molecule 4 (6.20 g, 6.00 mmol) in DCM (75 mL) is added a solution of 4N HCl in dioxane (15 mL) and the reaction medium is stirred for 18 h at room temperature and then concentrated under reduced pressure. A white solid of molecule Al is obtained after solubilization of the residue in DCM and concentration under reduced pressure.

Yield: 5.25 g (96%)

^X H NMR (CDsOD, ppm): 0.90 (6H); 1.21-2.46 (60H); 2.81-3.34 (6H); 3.34-3.77 (8H); 4.30-4.80 (3H).

LC / MS (ESI): 417.0; (calculated ([M + 2H] ²⁺ ): 416.9).

Example A2 - Molecule A2

Molecule 5: Product obtained by the reaction between myristoyl chloride and Lproline [000523] To a solution of L-proline (300.40 g, 2.61 mol) in 2 N aqueous sodium hydroxide (1.63 L) at 0 ° C is slowly added over 1 h of myristoyl chloride (322 g, 1.30 mol) dissolved in DCM (1.63 L). At the end of the addition, the reaction medium is raised to 20 ° C in 2 h and 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 min. 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 Na2SO4, filtered through cotton and then concentrated under reduced pressure. The residue is dissolved in heptane (315 mL) and 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 + HJ +): 651.5).

Molecule 6: Product obtained by the reaction between molecule 5 and L-Lysine [000524] By a process similar to that used for the preparation of molecule 2 and applied to molecule 5 (20.02 g, 61.5 mmol ) and with L-lysine (4.72 g, 32.29 mmol), a white solid of molecule 6 is obtained after recrystallization from ethyl acetate.

Yield: 12.30 g (53%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.26 (40H); 1.35-1.50 (6H); 1.50-2.10 (10H); 2.10-2.25 (4H); 3.01 (2H); 3.31-3.55 (4H); 4.10-4.40 (3H); 7.68 (0.6H); 7.97 (1H); 8.27 (0.4H); 12.50 (1H).

LC / MS (ESI): 761.8; (calculated ([M + H] ⁺ ): 761.6).

Molecule 7: Product obtained by the reaction between molecule 3 and molecule 6 [000525] By a process similar to that used for the preparation of molecule 4 and applied to molecule 3 (3.00 g, 8.68 mmol) and at molecule 6 (6.00 g, 7.89 mmol), a colorless oil of molecule 7 is obtained.

Yield: 5.71 g (66%)

¹ H NMR (CDsOD, ppm): 0.90 (6H); 1.23-2.48 (86H); 2.96-3.75 (14H); 4.30-4.56 (2H); 4.65-4.88 (1H).

Molecule A2 [000526] By a process similar to that used for the preparation of the molecule Al and applied to the molecule 7 (5.71 g, 5.24 mmol), a colorless oil of molecule A2 is obtained.

Yield: 5.19 g (99%)

^X H NMR (CDaOD, ppm): 0.90 (6H); 1.21-2.46 (68H); 2.81-3.32 (6H); 3.32-3.78 (8H); 4.31-4.82 (3H).

LC / MS (ESI): 445.1; (calculated ([M + 2H] ²⁺ ): 444.9).

Example A3 - A3 molecule

Molecule 8: Product obtained by the reaction between norspermidine and tertbutylphenylcarbonate [000528] To a solution of norspermidine (15 mL, 107.22 mmol) in DMF (70 mL) is slowly added a solution of tert-butylphenylcarbonate (49, 6 mL, 268.06 mmol) in DMF (37 mL) and the mixture is stirred at room temperature for 16 h. The reaction medium is concentrated under reduced pressure, the residue is taken up in water (200 mL) then acidified to pH 1.4 with an aqueous solution of 10% HCl. The aqueous phase is washed with methyl tert-butyl ether (MTBE, 2 x 500 mL), basified to pH 12 with a 10% aqueous sodium hydroxide solution, and the product is extracted with DCM (4 x 250 mL) . The combined organic phases are dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 8 is obtained after crystallization from heptane.

Yield: 27.97 g (79%)

NMR (CDCI ₃ , ppm): 1.44 (18H); 1.64 (4H); 2.64 (4H); 3.20 (4H); 5.16 (2H) LC / MS (ESI): 332.3; (calculated ([M + H] ⁺ ): 332.3).

Molecule 9: Product obtained by the reaction between molecule 6 and molecule 8 [000529] By a process similar to that used for the preparation of molecule 4 and applied to molecule 6 (18.00 g, 23.65 mmol) and at molecule 8 (9.41 g, 28.38 mmol), a colorless oil of molecule 9 is obtained.

Yield: 22.83 g (90%)

NMR M (DMSO-de, ppm): 0.85 (6H); 1.12-2.02 (80H); 2.02-2.30 (4H); 2.77-3.60 (14H); 4.16-4.41 (2H); 4.45-4.62 (1H); 6.59-6.94 (2H); 7.60-8.38 (2H).

LC / MS (ESI): 1075.3; (calculated ([M + H] ⁺ ): 1074.9).

Molecule A3 [000530] After a process similar to that used for the preparation of the molecule Al and applied to the molecule 9 (22.80 g, 21.22 mmol), the residue obtained is dissolved in DCM, the organic phase is washed with a 2N aqueous sodium hydroxide solution, dried over Na2SO4, filtered and concentrated in vacuo. A colorless solid of molecule A3 is obtained after solubilization of the residue in water (1.5 L) and lyophilization.

Yield: 17.76 g (96%)

NMR (DMSO-d6, ppm): 0.85 (6H); 1.13-2.28 (70H); 2.42-2.61 (4H); 2.83-3.61 (10H); 4.15-4.43 (2H); 4.52-4.73 (1H); 7.63-8.34 (2H).

LC / MS (ESI): 438.0, 874.9; (calculated ([M + 2H] ²⁺ ): 437.9, ([M + H] ⁺ ): 874.7).

Example A4: molecule A4

Molecule 10: Product obtained by the reaction between molecule 6 and [2- (2 aminoethoxy) ethoxy] acetic acid [000531] Λ a solution of molecule 6 (8.08 g, 10.61 mmol) in anhydrous DMF ( 65 mL) are added the NHS (1.23 g, 10.72 mmol) then the DCC (2.21 g, 10.72 mmol) and the medium is stirred at room temperature for 18 h. The mixture is filtered on a frit and then added slowly to a solution of [2- (2 aminoethoxy) ethoxy] acetic acid (1.78 g, 10.91) suspended in DMF (50 mL). After 24 h of stirring at room temperature, ethyl acetate (220 ml) and an aqueous 0.1N HCl solution (100 ml) are added. The organic phase is separated, washed with a saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo. A colorless oil of molecule 10 is obtained after purification by flash chromatography (eluent: DCM, methanol).

Yield: 4.90 g (51%)

^X H NMR (CDsOD, ppm): 0.90 (6H); 1.22-2.49 (62H); 3.09-3.29 (2H); 3.32-3.46 (2H); 3.46-3.61 (4H); 3.61-3.72 (6H); 4.13 (2H); 4.28-4.55 (3H); 7.83-8.26 (1H).

LC / MS (ESI): 906.8; (calculated ([M + H] ⁺ ): 906.7).

Molecule 11: Product obtained by the reaction between molecule 3 and molecule 10 [000532] By a process similar to that used for the preparation of molecule 4 applied to molecule 3 (2.24 g, 6.49 mmol) and to molecule 10 (4.90 g, 5.41 mmol) in solution in DMF (15 mL), a colorless oil of molecule 11 is obtained after purification by flash chromatography (eluent: DCM, methanol). Yield: 5.30 g (79%)

NMR ^X H (CDCl₃, ppm): 0.88 (6H); 1.20-2.37 (86H); 2.99-3.52 (14H); 3.52-3.72 (8H); 4.14-4.26 (2H); 4.35-4.57 (3H); 4.78-5.75 (2H); 7.00-7.57 (3H).

A4 molecule By a process similar to that used for the preparation of the molecule Al and applied to the molecule 11 (5.30 g, 4.29 mmol), a colorless oil of molecule A4 is obtained.

Yield: 4.30 g (99%)

NMR ^X H (CDCl₃, ppm): 0.88 (6H); 1.16-2.62 (68H); 2.95-3.93 (22H); 4.30-4.79 (5H); 7.52-8.67 (9H).

LC / MS (ESI): 517.8, 1033.8; (calculated ([M + 2H] ²⁺ ): 517.4, ([M + H] ⁺ ): 1033.8).

Example A5: molecule A5

Molecule 12: Product obtained by the reaction between molecule 6 and the methyl ester of / V-epsilon-tert-butyloxycarbonyl-L-Lysine (HLys (Boc) OMe) [000534] To a solution of molecule 6 (43, 00 g, 56.49 mmol) in THF (375 mL) are added at 0 ° C DIPEA (8.76 g, 67.79 mmol), HOBt (865 mg, 5.65 mmol) and l 'EDC (11.91 g, 62.14 mmol). After 15 min of stirring, the HLys (Boc) OMe (20.12 g, 67.79 mmol) is added and the reaction medium is stirred for 24 h at 0 ° C. The residue is concentrated under reduced pressure, taken up in ethyl acetate (300 mL) and the organic phase is washed with a saturated aqueous solution of NaHCO3 (150 mL), a 5% aqueous HCl solution (2 x 150 mL) then a saturated aqueous NaCl solution (2 x 150 mL). After drying over Na2SO4 and filtration, the medium is concentrated under reduced pressure. A transparent solid of molecule 12 is obtained.

Yield: 55.80 g (98%)

NMR (CDCh, ppm): 0.87 (6H); 1.18-1.74 (61H); 1.74-2.07 (8H); 2.07-2.38 (8H); 2.96-3.17 (3H); 3.30-3.50 (3H); 3.54-3.67 (2H); 3.71 (3H); 4.25-4.40 (1H); 4.44-4.63 (3H); 4.74-4.98 (1H); 7.10 (1H); 7.48 (1H); 7.65 (1H).

LC / MS (ESI): 1003.8 (calculated ([M + H] ⁺ ): 1003.8).

Molecule 13: Product obtained by saponification of the methyl ester of molecule 12 [000535] A solution of molecule 12 (55.8 g, 55.61 mmol) in THF / methanol 1: 1 (370 mL) is cooled to 0 ° C, then a solution of LiOH (2.0 g, 83.41 mmol) in water (185 mL) is added slowly. The reaction medium is stirred for 16 h at 0 ° C and then 30 min at room temperature. The residue is concentrated under reduced pressure, taken up in DCM (500 mL) and acidified with a 10% aqueous HCl solution to pH 1. DCM (500 mL) is added, the organic phase is separated and the aqueous phase is extracted with DCM (2 x 300 mL). The combined organic phases are washed with a saturated aqueous NaCl solution (2 x 300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 13 is obtained after crystallization from acetone.

Yield: 46.1 g (84%)

^X H NMR (Pyridine-ds, ppm): 0.88 (6H); 1.14-2.08 (67H); 2.08-2.68 (10H); 3,143.97 (8H); 4.55-5.22 (4H); 7.29-7.42 (1H); 8.28-8.59 (1H); 8.91-9.39 (2H). LC / MS (ESI): 989.8 (calculated ([M + H] ⁺ ): 989.8).

Molecule 14: Product obtained by the reaction between molecule 13 and ethylenediamine / V-Boc [000536] By a process similar to that used for the preparation of molecule 10 applied to molecule 13 (14.0 g, 14.15 mmol) in solution in DCM (94 mL) and in N-Boc ethylenediamine (2.72 g, 16.98 mmol), a white solid of molecule 14 is obtained after recrystallization from acetonitrile.

Yield: 13.80 g (86%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.10-2.34 (86H); 2.77-3.18 (8H); 3.27-3.68 (4H); 4.00-4.46 (4H); 6.26-6.84 (2H); 7.45-8.30 (4H).

LC / MS (ESI): 1131.8 (calculated ([M + HJ +): 1131.9).

Molecule A5 [000537] After a process similar to that used for the preparation of the molecule Al and applied to the molecule 14 (13.80 g, 12.19 mmol), the residue obtained is solubilized in DCM, the organic phase is washed with a 2N aqueous sodium hydroxide solution, dried over Na2SO4, filtered and concentrated in vacuo. A colorless solid of molecule A5 is obtained after recrystallization from acetonitrile.

Yield: 9.76 g (86%)

1 H NMR (DMSO-de, ppm): 0.85 (6H); 1.05-2.43 (72H); 2.43-2.60 (4H); 2.89-3.14 (4H); 3.28-3.64 (4H); 4.00-4.46 (4H); 7.49-8.31 (4H).

LC / MS (ESI): 466.4, 931.8 (calculated ([M + 2H] ²⁺ ): 466.4, ([M + HJ +): 931.8).

Example A6: molecule A6

Molecule 15: Product obtained by the reaction between molecule 5 and W-epsilon-tertbutyloxycarbonyl-L-Lysine (HLys (Boc) OH) [000538] By a process similar to that used for the preparation of molecule 1 applied to the molecule 5 (37.00 g, 113.67 mmol) and with (HLys (Boc) OH) (30.80 g, 125.04 mmol), a white solid of molecule 15 is obtained after concentration of the reaction medium under pressure reduced, solubilization of the residue in water (500 mL), washing of the aqueous phase with ethyl acetate (2 x 250 mL) then acidification to pH 1 and filtration of the precipitate formed.

Yield: 61.83 g (98%)

^X NMR (DMSO-de, ppm): 0.85 (3H); 1.13-2.05 (41H); 2.05-2.28 (2H); 2.81-2.95 (2H); 3.23-3.55 (2H); 4.07-4.15 (0.5H); 4.15-4.23 (0.5H); 4.30-4.40 (1H); 6,306.84 (1H); 7.99 (0.5H); 8.28 (0.5H); 12.51 (1H).

LC / MS (ESI): 554.4 (calculated ([M + H] ⁺ ): 554.4).

Molecule 16: product obtained by the reaction between molecule 15 and tri (ethylene glycol) diamine [000539] To a solution of molecule 15 (45.00 g, 81.26 mmol) in DCM (540 mL) and at 0 ° C are successively added HOBt (1.24 g, 8.13 mmol), tri (ethylene glycol) diamine (6.02 g, 40.63 mmol) then EDC (17.14 g, 89.38 mmol) . The reaction mixture is stirred for 1 h at 0 ° C and then 15 h at room temperature. The medium is washed with a saturated aqueous NaHCO3 solution (2 x 250 mL), a 1N aqueous HCl solution (2 x 250 mL), a saturated aqueous NaCl solution (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. A colorless solid of molecule 16 is obtained.

Yield: 47.02 g (95%)

NMR (DMSO-de, ppm): 0.85 (6H); 1.11-2.32 (86H); 2.80-2.92 (4H); 3.12-3.28 (4H); 3.28-3.59 (12H); 4.08-4.19 (1.3H); 4.19-4.34 (2H); 4.34-4.46 (0.7H); 6.32-6.81 (2H); 7.64-7.74 (1.3H); 7.74-7.83 (1.3H); 7.93-8.00 (0.7H); 8.11-8.18 (0.7H).

LC / MS (ESI): 1220.0 (calculated ([M + H] ⁺ ): 1219.9).

A6 molecule By a process similar to that used for the preparation of the A5 molecule and applied to the molecule 16 (23.00 g, 18.86 mmol), a white solid of the A6 molecule is obtained.

Yield: 16.43 g (85%)

NMR (DMSO-de, ppm): 0.85 (6H); 1.11-2.05 (68H); 2.08-2.31 (4H); 2.44-2.54 (4H); 3.10-3.58 (16H); 4.08-4.18 (1.3H); 4.22-4.32 (2H); 4.37-4.46 (0.7H);

7.66-7.87 (2.6H); 7.96-8.06 (0.7H); 8.13-8.23 (0.7H).

LC / MS (ESI): 510.5, 1020.0 (calculated ([M + 2H] ²⁺ ): 510.4, ([M + H] ⁺ ): 1019.8).

Example A7: molecule A7

Molecule 17: Product obtained by the reaction between molecule 5 and / V-beta (tert-butyloxycarbonyl) -L-2,3-diaminopropionic acid (HDap (Boc) OH) [000541] By a process similar to that used for the preparation of molecule 1 applied to molecule 5 (100.00 g, 307.23 mmol) and to HDap (Boc) OH (65.88 g, 322.59 mmol), a white solid of molecule 17 is obtained after concentration of the organic phase under reduced pressure. This is used directly without further purification.

Yield: 141.6 g (90%)

NMR (CDCh, ppm): 0.87 (3H); 1.18-1.49 (29H); 1.54-1.68 (2H); 1.82-2.41 (6H); 3.37-3.78 (4H); 4.31-4.74 (2H); 5.61 (1H); 7.63 (1H); 9.59 (1H).

LC / MS (ESI): 512.2 (calculated ([M + H] ⁺ ): 512.4).

Molecule 18: Product obtained by the reaction between molecule 17 and ethylenediamine [000542] By a process similar to that used for the preparation of molecule 16 and applied to molecule 17 (41.00 g, 80.12 mmol) and with ethylenediamine (2.41 g, 40.06 mmol) in the presence of DIPEA (20.71 g, 160.25 mmol), a white solid of molecule 18 is obtained after recrystallization from acetonitrile.

Yield: 40.80 g (97%)

^Χ N NMR (DMSO-de, ppm): 0.85 (6H); 1.16-2.40 (74H); 2.97-3.63 (12H); 4,114.25 (3H); 4.25-4.41 (1H); 6.54-6.79 (2H); 7.58-8.07 (4H).

LC / MS (ESI): 1047.8 (calculated ([M + HJ +): 1047.8).

A7 molecule By a process similar to that used for the preparation of the A5 molecule and applied to the molecule 18 (35.90 g, 34.27 mmol), a white solid of the A7 molecule is obtained.

Yield: 16.43 g (85%)

1 H NMR (DMSO-de, ppm): 0.85 (6H); 1.12-1.55 (48H); 1.67-2.31 (12H); 2,642.82 (4H); 2.99-3.25 (4H); 3.25-3.61 (4H); 4.02-4.12 (1.4H); 4.12-4.22 (0.6H); 4.22-4.34 (1.4H); 4.38-4.45 (0.6H); 7.70-8.20 (4H).

LC / MS (ESI): 424.4, 847.7 (calculated ([M + 2H] ²⁺ ): 424.4, ([M + H] ⁺ ): 847.7).

Example AS: molecule A8

Molecule 19: Product obtained by the reaction between molecule 15 and ethylenediamine [000544] By a process similar to that used for the preparation of molecule 18 applied to molecule 15 (16.05 g, 29.0 mmol) and with ethylenediamine (0.96 g, 16.0 mmol), a white solid of molecule 19 is obtained after recrystallization from acetonitrile.

Yield: 19.78 g (60%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.09-2.38 (86H); 2.80-2.91 (4H); 3.00-3.60 (8H); 4.04-4.15 (1.3H); 4.15-4.23 (0.7H); 4.23-4.31 (1.3H); 4.36-4.45 (0.7H); 6.27-6.82 (2H); 7.60-8.21 (4H).

LC / MS (ESI): 1131.8, 1153.8 (calculated ([M + HJ +): 1131.9, ([M + Na] ⁺ ): 1153.9).

Molecule A8 By a process similar to that used for the preparation of the molecule Al and applied to the molecule 19 (19.78 g, 17.48 mmol), a white solid of molecule A8 is obtained after solubilization of the residue in water, addition of a 2N aqueous sodium hydroxide solution until a precipitate is formed, filtration and drying under reduced pressure.

Yield: 9.93 g (61%)

¹ H NMR (CDCIs, ppm): 0.88 (6H); 1.16-2.25 (68H); 2.25-2.39 (4H); 2.65-2.83 (4H); 3.22-3.54 (6H); 3.54-3.74 (2H); 4.23-4.37 (2H); 4.43-4.58 (2H); 7.40 (2H); 7.63 (2H).

LC / MS (ESI): 466.7, 931.8 (calculated ([M + 2H] ²⁺ ): 466.4, ([M + HJ +): 931.8).

Example A9: molecule A9

Molecule 20: Product obtained by the reaction between molecule 17 and 4,7,10-trioxa1,13-tridecanediamine [000546] By a process similar to that used for the preparation of molecule 18 applied to molecule 17 (32, 00 g, 62.54 mmol) and with 4,7,10-trioxa-1,13tridecanediamine (6.89 g, 31.27 mmol), a white solid of molecule 20 is obtained. Yield: 29.23 g (77%)

NMR (DMSO-de, ppm): 0.85 (6H); 1.17-2.38 (78H); 3.01-3.15 (4H); 3.15-3.62 (20H); 4.09-4.24 (3H); 4.28-4.40 (1H); 6.58-6.87 (2H); 7.41-8.03 (4H).

LC / MS (ESI): 1207.9 (calculated ([M + H] +): 1207.9).

A9 molecule By a process similar to that used for the preparation of the A5 molecule and applied to the molecule 20 (28.30 g, 23.43 mmol), a white solid of the A9 molecule is obtained.

Yield: 15.76 g (67%)

NMR (DMSO-de, ppm): 0.85 (6H); 1.10-2.33 (64H); 2.60-2.86 (4H); 3.01-3.19 (4H); 3.27-3.62 (16H); 4.01-4.13 (1.4H); 4.13-4.20 (0.6H); 4.20-4.30 (1.4H); 4.36-4.46 (0.6H); 7.57-7.70 (1.4H); 7.70-7.85 (1.4H); 7.91-8.03 (0.6H); 8,038.19 (0.6H).

LC / MS (ESI): 504.4, 1007.9 (calculated ([M + 2H] ²⁺ ): 504.4, ([M + HJ +): 1007.8).

Example A1O: molecule A1O

Molecule 21: Product obtained by the reaction between molecule 8 and molecule 13 [000548] By a process similar to that used for the preparation of molecule 4 applied to molecule 8 (7.12 g, 21.47 mmol) and with molecule 13 (17.70 g, 17.89 mmol), with stirring between 0 ° C. and room temperature for 16 h, a white foam of molecule A10 is obtained after washing the reaction medium in dichloromethane with a saturated aqueous solution in NaHCO3 (2 x 100 mL), 10% aqueous HCl solution (2 x 100 mL), saturated aqueous NaCl solution (50 mL), drying over Na2SO4, filtration and concentration in vacuo.

Yield: 20.10 g (86%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.11-2.04 (95H); 2.04-2.32 (4H); 2.76-3.61 (16H); 4.09-4.62 (4H); 6.26-7.01 (3H); 7.57-8.43 (3H).

LC / MS (ESI): 1303.1, 1325.1 (calculated ([M + H] ⁺ ): 1303.0, ([M + Na] ⁺ ): 1325.0).

Molecule A10 [000549] By a process similar to that used for the preparation of the molecule A5 and applied to the molecule 21 (20.10 g, 15.43 mmol), a pale yellow solid of molecule A10 is obtained.

Yield: 10.70 g (69%)

1 H NMR (DMSO-de, ppm): 0.85 (6H); 1.11-2.31 (78H); 2.41-2.70 (6H); 2.87-3.68 (10H); 4.06-4.50 (3H); 4.56-4.77 (1H); 7.59-8.35 (3H).

LC / MS (ESI): 501.9, 1002.7 (calculated ([M + 2H] ²⁺ ): 501.9, ([M + H] ⁺ ): 1002.8).

Example Garlic: Ali molecule

Molecule 22: Product obtained by the reaction of molecule 6 and a-tert-butyl-ybenzyl L-glutamate [000550] By a process similar to that used for the preparation of molecule 12 applied to molecule 6 (5.0 g, 6.57 mmol) in solution in chloroform (34 mL) and with α-tert-butyl-y-benzyl L-glutamate (2.167 g, 6.57 mmol), a white solid of molecule 22 is obtained after purification by flash chromatography (eluent: DCM, MeOH).

Yield: 6.16 g (90 ° / o)

H NMR ^J (CDCl₃, ppm): 0.88 (6H); 1.18-2.51 (75H); 2.89-3.68 (6H); 4.18-4.66 (4H); 5.11 (2H); 7.11 (1H); 7.28-7.41 (5H); 7.55 (1H); 7.70 (1H).

LC / MS (ESI): 1037.0 (calculated ([M + H] ⁺ ): 1036.8).

Molecule 23: Product obtained by the reaction between molecule 22 and HCl [000551] To a solution of molecule 22 (6.16 g, 5.94 mmol) in DCM (60 mL) is added a solution of HCl 4 N in dioxane (15 mL). After 48 h at room temperature, the reaction medium is concentrated under reduced pressure and the residue is purified by flash chromatography (eluent: DCM, MeOH).

Yield: 3.05 g (51%)

1 H NMR (CDCh, ppm): 0.88 (6H); 1.14-2.58 (66H); 2.98-3.69 (6H); 4.24-4.61 (4H); 5.10 (2H); 7.27-7.40 (5H); 6.75-7.60 (3H).

LC / MS (ESI): 980.8 (calculated ([M + HJ +): 980.7).

Molecule 24: Product obtained by the reaction between molecule 23 and molecule 3 [000552] By a process similar to that used for the preparation of molecule 4 applied to molecule 23 (1.5 g, 1.53 mmol) and to molecule 3 (0.582 g, 1.683 mmol) in solution in chloroform (23 mL), a colorless oil of molecule 24 is obtained after purification by flash chromatography (eluent: DCM, methanol). Yield: 1.54 g (77%)

^X H NMR (CDCIa, ppm): 0.88 (6H); 1.18-2.53 (90H); 2.85-3.68 (14H); 4.24-4.63 (3H); 4.80-4.98 (1H); 5.06-5.21 (2H); 7.28-7.39 (5H).

Ail molecule By a process similar to that used for the preparation of the molecule Al and applied to the molecule 24 (1.54 g, 1.18 mmol), a white solid of the hydrochloride of the molecule Ail is obtained.

Yield: 1.32 g (95%)

NMR (CDs OD, ppm): 0.90 (6H); 1.17-2.28 (66H); 2.34-3.60 (6H); 2.84-3.07 (4H); 3.07-3.29 (2H); 3.37-3.80 (8H); 4.16-4.46 (3H); 4.84-4.98 (1H); 5.14 (2H); 7.30-7.40 (5H).

LC / MS (ESI): 554.7; 1108.0; (calculated ([M + 2H] ²⁺ ): 554.4; ([M + H] ⁺ ); 1107.9).

Example A12: molecule A12

Molecule 25: Product obtained by the reaction between Fmoc-Lys (Fmoc) -OH and 2-CI-trityl chloride resin [000554] To a suspension of Fmoc-Lys (Fmoc) -OH (7.32 g, 12, 40 mmol) in dichloromethane (60 mL) at room temperature is added DIPEA (4.32 mL, 24.80 mmol). After complete solubilization (10 min), the solution obtained 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 reactor suitable for 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 min. The resin is filtered, washed successively with dichloromethane (3 x 60 mL), DMF (2 x 60 mL), dichloromethane (2 x 60 mL), isopropanol (1 x 60 mL) and dichloromethane (3 x 60 mL).

Molecule 26: Product obtained by reaction between molecule 25 and a DMF / piperidine 80:20 mixture [000555] Molecule 25, previously washed with DMF, is treated with a DMF / piperidine 80:20 mixture (60 mL). After 30 min 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).

Molecule 27: Product obtained by the reaction between molecule 26 and FmocGlu (OtBu) -OH [000556] To a suspension of Fmoc-Glu (OtBu) -OH (10.55 g, 24.80 mmol) and l- [bis (dimethylamino) methylene] -lH-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 9.43 g, 24.80 mmol) in a DMF / dichloromethane 1 mixture: 1 (60 mL) is added DIPEA (8.64 mL, 49.60 mmol). After complete solubilization, the solution obtained is poured onto molecule 26. 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).

Molecule 28: Product obtained by the reaction between molecule 27 and a 50:50 DMF / morpholine mixture [000557] Molecule 27, previously washed with DMF, is treated with a 50:50 DMF / morpholine mixture (60 ml). After 1 h 15 min 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).

Molecule 29: Product obtained by the reaction between molecule 28 and molecule 5 [000558] By a process similar to that used for molecule 27 applied to molecule 28 and to molecule 5 (8.07 g, 24.80 mmol ) in DMF (60 mL), molecule 29 is obtained.

Molecule 30: Product obtained by the reaction between molecule 29 and a mixture of dichloromethane / l, l, l, 3,3,3-hexafluoro-2-propanol (HFIP) 80:20 [000559] Molecule 29 is treated with a dichloromethane / l, l, l, 3,3,3-hexafluoro-2-propanol (HFIP) 80:20 mixture (60 mL). After 20 min of stirring at room temperature, the resin is filtered and washed with dichloromethane (2 x 60 mL). The solvents are evaporated under reduced pressure. Two co-evaporations are then carried out on the residue with dichloromethane (60 ml) then diisopropyl ether (60 ml). The product is purified by chromatography on silica gel (dichloromethane, methanol). A white solid of molecule 30 is obtained.

Yield: 2.92 g (52% over 6 steps)

NMR M (CDs OD, ppm): 0.90 (6H); 1.22-2.47 (88H); 3.13-3.25 (2H); 3.45-3.76 (4H); 4.24-4.55 (5H).

LC / MS (ESI +): 1131.9 (calculated ([M + HJ +): 1131.8).

Molecule 31: Product obtained by the reaction between molecule 30 and molecule 3 [000560] By a process similar to that used for the preparation of molecule 4 applied to molecule 30 (3.12 g, 2.76 mmol) and to molecule 3 (1.048 g, 3.03 mmol) dissolved in chloroform (40 mL), a colorless oil of molecule 31 is obtained after purification by flash chromatography (eluent: DCM, methanol). Yield: 2.57 g (64%)

^X H NMR (CDsOD, ppm): 0.90 (6H); 1.21-2.47 (112H); 2.82-3.74 (14H); 4.16-4.53 (4H); 4.53-4.78 (1H).

Molecule A12 By a process similar to that used for the preparation of the molecule Al and applied to the molecule 31 (2.56 g, 1.75 mmol), a white solid of the hydrochloride of the molecule A12 is obtained. This is dissolved in water (40 mL) by adding 1 N NaOH solution until a pH 7 is reached, then the solution is lyophilized to give a white solid of the molecule A12.

Yield: 2.1 g (95%)

NMR ^{Χ Η} (CDaOD, ppm): 0.90 (6H); 1.19-2.32 (68H); 2.32-2.54 (8H); 2.82-3.15 (4H); 3.15-3.79 (10H); 4.23-4.76 (5H).

LC / MS (ESI): 1146.9; (calculated ([M + H] ⁺ ): 1146.8).

Part B - Synthesis of hydrophobic co-polyamino acids [000562] The hydrophobic co-polyamino acids are shown in the Table

2.

Co- polyamino Structure NaO JO O ^^ ONa bl AT" . JxJ Jx 1 ^R 1 A NH] Il m II n OO i ’= j0.022, DP (m + n) = 45

* \ Χ ^χ Χ > XX NH ; O 'NOT' / XH X *. * O X C1X23 x = VS O oh AT 11 ^ 23 Ri = H or pyroglutamate NaO. ° X AT We have r R. W X | pm he not O O i '= 0.045, DP (m + n) = 22 * X X .NH N H Χ'Γ ^ ' B2 XX XH „ -o vs X Xy T 0 Λ AT Ν ' / X = ) vs Ο _ή Η ₂ 3 1 ° X / ^NH O ό AT vs 11 * ^ 23 Ri = H or pyroglutamate

NaO ^ CX .ONa Ύ R, [Λ \ Τ ^χ - r A ~ PR | : not t ^NH U T ^NH o 0 i '= 0.05, DP (m + n) = 20 NH / * »* B3 Λ "NH T o J Λ \ / AT x = C ₁₃ H ₂ 7 Ύ I NH O AT n / A : Lj vs ^1:27 p.m. Ri = H or pyroglutamate NaO ^^ O We have B4 rX J. [NH | pm r A ^nh . X not O 0 i '= 0.022, DP (m + n) = 46

100

101 i '= 0.056, DP (m + n) = 18

Ri = H or pyroglutamate

i '= 0.043, DP (m + n) = 23

i = u, ua, ur - zu

102

103

BII

Ο ο i - 0.042, DP (m + n) = 24

Ri = H or pyroglutamate

B12

i '= 0.05, DP (m + n) = 20

Ri = H or pyroglutamate

104

B13

i '= 0.037, DP (m + n + p) = 27

Ri = H or pyroglutamate

B14

Ri = H or pyroglutamate i '= 0.026, DP (m + n) = 38

CO.Na

105

B15 NaCL O ₅ ,We have s 1 ^R 1 t ^NH AT üî ^NH I It m η | Y · O o Ri = H or pyroglutamate i ’= 0.042, DP (m + n) = 24 J H Γ Y ^{N 0} cY ^C U ^H 2 ·· J _Q T -...... τά. co ^ SrY> ° cA _t3 H _2Z x = 3O-Na

Table 2: list of hydrophobized co-polyamino acids.

Example B1:

Co-polyamino acid B1 - sodium poly-L-glutamate modified by the molecule Al and having a number-average molar mass (Mn) of 6850 g / mol [000563] The hydrochloride salt of the molecule is successively introduced into a suitable container Al (3.70 g, 4.09 mmol), chloroform (40 mL), 4 Â molecular sieve (1.5 g), as well as Amberiite IRN 150 ion exchange resin (1.5 g) . After 2 h 30 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 (5 mL) to be used directly in the next reaction.

In a flask previously dried in an oven, y-benzyl-L-glutamate / V-carboxyanhydride (43.04 g, 163.50 mmol) is placed under vacuum for 2 h and then anhydrous DMF (80 mL ) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of molecule Al, 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 room temperature then poured dropwise into diisopropyl ether (3.2 L) with stirring. The white precipitate is recovered

106 by filtration, washed twice with diisopropyl ether (150 mL), then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in trifluoroacetic acid (152 mL), and a 33% solution of HBr in acetic acid (106 mL) is then added dropwise and at 0 ° C. The solution is stirred for

2 h at room temperature then poured dropwise on a 1: 1 (v / v) mixture of diisopropyl ether / water with stirring (1.8 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 / water (150 ml), then with water (150 ml). The solid obtained is dissolved in water 10 (750 mL), the pH is adjusted to 7.5 by adding a 1N aqueous sodium hydroxide solution, then the theoretical polymer concentration is adjusted to 20 g / L by addition of water. The mixture is filtered on a 0.45 μm filter, then is purified by ultrafiltration against a 0.9% NaCl solution, then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7.0. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 25.8 mg / g

DP (estimated by ¹ H NMR) = 45 therefore the ratio j / (m + n) = 0.022, said ratio j / (m + n) being called i '.

The calculated average molar mass of co-polyamino acid B1 is 7552 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 6850 g / mol.

Example B2:

Co-polyamino acid B2 - sodium poly-L-glutamate modified by the molecule Al and having a number average molar mass (Mn) of 3330 g / mol [000565] By a process similar to that used for the preparation of the copolyamino acid B1 applied with the hydrochloride salt of the molecule Al (4.76 g, 5.26 mmol) and with y-benzyl-L-glutamate / V-carboxyanhydride (27.68 g, 105.1 mmol), a poly-L-glutamate of sodium modified by the molecule Al is obtained.

Dry extract: 25.6 mg / g

DP (estimated by NMR ’Ή) = 22 so i '= 0.045

The calculated average molar mass of the co-polyamino acid B2 is 4076 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3330 g / mol.

107

Example B3:

Co-polyamino acid B3 - sodium poly-L-glutamate modified by the molecule A2 and having a number-average molar mass (Mn) of 3360 g / mol [000566] By a process similar to that used for the preparation of the copolyamino acid B1 applied with the hydrochloride salt of the molecule A2 (4.90 g, 5.10 mmol) and with γ-benzyl-L-glutamate / V-carboxyanhydride (26.83 g, 101.9 mmol), a co-poly-L -sodium glutamate modified by the molecule Α2 is obtained.

Dry extract: 29.7 mg / g

DP (estimated by NMR ^J H) = 20 therefore i '= 0.05

The calculated average molar mass of co-polyamino acid B3 is 3830 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3360 g / mol.

Example B4:

Co-polyamino acid B4 - sodium poly-L-glutamate modified by the molecule A2 and having a number average molar mass (Mn) of 7050 g / mol [000567] By a process similar to that used for the preparation of the copolyamino acid B1 applied with the hydrochloride salt of the molecule Α2 (5.90 g, 6.14 mmol) and with γ-benzyl-L-glutamate / V-carboxyanhydride (64.63 g, 245.50 mmol), a co-poly-L -sodium glutamate modified by the molecule A2 is obtained.

Dry extract: 24.1 mg / g

DP (estimated by NMR ^Χ Η) = 46 therefore i '= 0.022

The calculated average molar mass of co-polyamino acid B4 is 7759 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 7050 g / mol.

Example B5:

Co-polyamino acid B5 - sodium poly-L-glutamate modified by the molecule

A2 and having a number-average molar mass (Mn) of 10,440 g / mol [000568] By a process similar to that used for the preparation of copolyamino acid B1 applied to the hydrochloride salt of the molecule A2 (3.09 g, 3, 21 mmol) and with γ-benzyl-L-glutamate / V-carboxyanhydride (52.09 g, 197.9 mmol), a sodium co-poly-L-glutamate modified by the molecule A2 is obtained.

Dry extract: 27.2 mg / g

DP (estimated by NMR ^X H) - 66 thus i '- 0.015

The calculated average molar mass of co-polyamino acid B5 is 10781 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 10440 g / mol.

108

Example B6:

Co-polyamino acid B6 - sodium poly-L-glutamate modified by the molecule A3 and having a number-average molar mass (Mn) of 3020 g / mol [000569] By a process similar to that used for the preparation of the copolyamino acid Bl applied to molecule A3 in the form of free amine (4.15 g, 4.75 mmol) and to y-benzyl-L-glutamate / V-carboxyanhydride (25.0 g, 95.0 mmol), a copoly-L -sodium glutamate modified by the molecule A3 is obtained.

Dry extract: 20.4 mg / g

DP (estimated by NMR * H) = 18 therefore i * = 0.056

The calculated average molar mass of co-polyamino acid B6 is 3514 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn - 3020 g / mol.

Example B7:

Co-polyamino acid B7 - sodium poly-L-glutamate modified by the molecule A4 and having a number-average molar mass (Mn) of 3360 g / mol [000570] By a process similar to that used for the preparation of the copolyamino acid Bl applied to the molecule A4 in the form of free amine (2.06 g, 1.99 mmol) and to y-benzyl-L-glutamate / V-carboxyanhydride (10.5 g, 39.9 mmol), a copoly-L -sodium glutamate modified by the molecule A4 is obtained.

Dry extract: 17.6 mg / g

DP (estimated by ¹ H NMR) = 23 therefore i '= 0.043

The calculated average molar mass of co-polyamino acid B7 is 4429 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn ~ 3360 g / mol.

Example BS:

Co-polyamino acid BS - sodium poly-L-glutamate modified by the molecule AS and having a number-average molar mass (Mn) of 3360 g / mol [000571] By a process similar to that used for the preparation of the copolyamino acid Bl applied to the molecule A5 in the form of free amine (3.89 g, 4.18 mmol) and to y-benzyl-L-glutamate / V-carboxyanhydride (22.00 g, 84.00 mmol), a co-poly -Sodium glutamate modified by the molecule A5 is obtained.

Dry extract: 17.9 mg / g

DP (estimated by 1 H-NMR) = 20 therefore i '~ 0.050

The calculated average molar mass of co-polyamino acid B8 is 3873 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3360 g / mol.

109

Example Β9:

Co-polyamino acid B9 - sodium poly-L-glutamate modified by the molecule

A6 and having a number-average molar mass (Mn) of 3340 g / mol [000572] By a process similar to that used for the preparation of copolyamino acid B1 applied to the molecule A6 in the form of free amine (5.81 g, 5.70 mmol) and with γ-benzyl-L-glutamate / V-carboxyanhydride (30.00 g, 114 mmol), a sodium copoly-L-glutamate modified with the molecule A6 is obtained.

Dry extract: 16.4 mg / g

DP (estimated by NMR ^X H) = 20 therefore i = 0.05

The calculated average molar mass of co-polyamino acid B9 is 3961 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3340 g / mol.

ORGANIC example:

BIO co-polyamino acid - sodium poly-L-glutamate modified by the molecule A7 and having a number-average molar mass (Mn) of 2920 g / mol [000573] By a process similar to that used for the preparation of copolyamino acid B1 applied to the molecule A7 in the form of free amine (3.54 g, 4.18 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (22.00 g, 84.00 mmol), a co-poly -Sodium glutamate modified by the molecule A7 is obtained.

Dry extract: 18.4 mg / g

DP (estimated by ¹ H NMR) = 20 therefore i '= 0.05

The calculated average molar mass of co-polyamino acid B10 is 3789 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2920 g / mol.

Example Bll:

Co-polyamino acid Bll - sodium poly-L-glutamate modified by the molecule AS and having a number-average molar mass (Mn) of 3750 g / mol [000574] By a process similar to that used for the preparation of the copolyamino acid B1 applied to the molecule A8 in the form of free amine (2.51 g, 2.69 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (14.19 g, 53.90 mmol), a co-poly -L-sodium glutamate modified by the molecule A8 is obtained.

Dry extract: 20.9 mg / g

DP (estimated by NMR ^Χ Η) = 24 therefore i '= 0.042

The calculated average molar mass of the co-polyamino acid B11 is 4478 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3750 g / mol.

110

Example B12:

Co-polyamino acid B12 - sodium poly-L-glutamate modified by the molecule A9 and having a number-average molar mass (Mn) of 3660 g / mol [000575] By a process similar to that used for the preparation of copolyamino acid B1 applied to the molecule A9 in the form of free amine (4.21 g, 4.18 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (22.00 g, 84.00 mmol), a co-poly -Sodium glutamate modified by the molecule A9 is obtained.

Dry extract: 18.6 mg / g

DP (estimated by NMR ^X H) = 20 therefore i '= 0.050

The calculated average molar mass of co-polyamino acid B12 is 3949 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3660 g / mol.

Example B13:

Co-polyamino acid B13 - sodium poly-L-glutamate modified by the molecule A1O and having a number-average molar mass (Mn) of 4170 g / mol [000576] By a process similar to that used for the preparation of the copolyamino acid B1 applied to the molecule A10 in the form of free amine (3.81 g, 3.80 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (30.00 g, 114.00 mmol), a co-poly -L-sodium glutamate modified by the molecule A10 is obtained.

Dry extract: 22.3 mg / g

DP (estimated by NMR ^X H) = 27 therefore i '= 0.037

The calculated average molar mass of the co-polyamino acid B13 is 4962 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 4170 g / mol.

Example B14:

Co-polyamino acid B14 - sodium poly-L-glutamate modified by the molecule Ail and having a number-average molar mass (Mn) of 6500 g / mol [000577] By a process similar to that used for the preparation of copolyamino acid B1 applied with the hydrochloride of the molecule Ail (1.21 g, 1.09 mmol) and with γ-benzyl-L-glutamate / V-carboxyanhydride (10.8 g, 41.0 mmol), a sodium co-poly-Lglutamate modified by the Ail molecule is obtained.

Dry extract: 22.2 mg / g

DP (estimated by NMR ^X H) = 38 therefore i '= 0.026

The calculated average molar mass of co-polyamino acid B14 is 6701 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 6500 g / mol.

111

Example B15:

Co-polyamino acid B15 - sodium poly-L-glutamate modified by the molecule A12 and having a number-average molar mass (Mn) of 4300 g / mol [000578] By a process similar to that used for the preparation of the copolyamino acid Bl applied to the molecule A12 in the form of free amine (2.00 g, 1.58 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (8.34 g, 31.7 mmol), a copoly-L -sodium glutamate modified by the molecule A12 is obtained.

Dry extract: 15.1 mg / g

DP (estimated by NMR ⁴ Η) = 24 therefore i '= 0.042

The calculated average molar mass of co-polyamino acid B14 is 4737 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 4300 g / mol.

Part Ç_ ^ Composition _? çQmm rcial ^. ^ s

Example C1: Rapid analog insulin solution (Humalog®) at 100 U / mL [000579] This solution is a commercial insulin lispro solution sold by the company ELI LILLY under the name of Humalog®. This product is a rapid analog insulin. The excipients in Humalog® are meta-cresol (3.15 mg / mL), glycerol (16 mg / mL), disodium phosphate (1.88 mg / mL), zinc oxide (to have 0 , 0197 mg of zinc ion / mL), sodium hydroxide and hydrochloric acid for adjusting the pH (pH 7-7.8) and water.

Example C2: Rapid analog insulin solution (NovoLog®) at 100 U / mL [000580] This solution is a commercial insulin aspart solution marketed by the company NOVO NORDISK under the name NovoLog® in the United States of America and Novorapid ® in Europe. This product is a rapid analog insulin. The excipients of Novolog® are glycerin (16 mg / mL), phenol (1.50 mg / mL), meta-cresol (1.72 mg / mL, zinc (19.6 pg / mL), disodium phosphate dihydrate (1.25 mg / mL), sodium chloride (0.5 mg / mL), sodium hydroxide and hydrochloric acid for pH adjustment (pH 7.2-7, 6) and water.

Example C3: Rapid analog insulin solution (Apidra®) at 100 U / ml This solution is a commercial insulin glulisine solution marketed by the company SANOFI under the name of Apidra®. This product is a rapid analog insulin. The excipients of Apidra® are meta-cresol (3.15 mg / mL),

112 tromethamine (6 mg / mL), sodium chloride (5 mg / mL), polysorbate 20 (0.01 mg / mL), sodium hydroxide and hydrochloric acid for pH adjustment ( pH 7.3) and water.

Example C4: Slow analog insulin solution (Lantus®) at 100 U / ml This solution is a commercial insulin glargine solution marketed by the company SANOFI under the name of Lantus®. This product is a slow analog insulin. The excipients in Lantus® are zinc chloride (30 pg / mL), meta-cresol (2.7 mg / mL), glycerol (85%) (20 mg / mL), sodium hydroxide and l hydrochloric acid for pH adjustment (pH 4) and water.

Example C5: Human insulin solution (ActRapid®) at 100 IU / mL This solution is a commercial solution of human insulin from NOVO NORDÏSK sold under the name of ActRapid®. This product is human insulin. The excipients of ActRapid® are zinc chloride, glycerol, meta-cresol, sodium hydroxide and hydrochloric acid for pH adjustment (pH 6.9-7.8) and water .

Example C6: Solution of human insulin (Umuline rapid®) at 100 IU / mL [000584] This solution is a commercial solution of human insulin from ELI LILLY sold under the name of Umuline rapid®. This product is human insulin. The excipients of Umuline Rapide® are glycerol, meta-cresol, sodium hydroxide and hydrochloric acid for pH adjustment (pH 7.0-7.8) and water.

Part.ÇA - Çotppositior> s_comRrenant de l ^ nsuline.flhrgine [000585] CAI preparation process: Preparation of a diluted copolyamino acid / insulin glargine 50 U / mL at pH 7.1, according to a process using insulin glargine liquid form (in solution) and a co-polyamino acid in liquid form (in solution).

Concentrated solutions of m-cresol and glycerin are added to a stock solution of co-polyamino acid at pH 7.1 so as to obtain a solution of co-polyamino acid with a concentration of co-poiyamino acid / excipients (mg / mL). ). The amount of excipients added is adjusted so as to obtain a concentration of m-cresol of 35 mM and glycerin of 184 mM in the co-polyamino acid composition! insulin glargine 50 U / mL at pH 7.1.

In a sterile jar, a Vinsse glargine volume of a commercial insulin glargine solution marketed under the name of Lantus® at a concentration of

113

100 U / mL is added to a volume V co-poiyamino acid / excipients of a copolyamino acid solution at the C co-polyamino acid / excipients concentration (mg / mL) so as to obtain a diluted co-polyamino acid C co-polyamino acid composition ( mg / ml _) / insulin glargine 50 U / ml at pH 7.1. A disorder appears. The pH is adjusted to pH 7.1 by adding concentrated NaOH and the solution is placed in a static oven in an oven at 40 ° C for 2 h until complete dissolution. This visually clear solution is placed at + 4 ° C.

Preparation process CA2: Preparation of a copolyamino acid / insulin glargine composition concentrated at pH 7.1 using a copolyamino acid, according to a process for concentrating a diluted composition.

A co-polyamino acid / insulin glargine 50 U / ml composition at pH 7.1 described in Example CAI is concentrated by ultrafiltration on a 3 kDa membrane made of regenerated cellulose (Amicon® Ultra-15 sold by the company Millipore) . At the end of this ultrafiltration step, the retentate is clear and the insulin glargine concentration in the composition is determined by reverse phase chromatography (RP-HPLC). The insulin glargine concentration in the composition is then adjusted to the desired value by dilution in a solution of m-cresol / glycerin excipients so as to obtain a final m-cresol concentration of 35 mM and an osmolarity of 300 mOsm / kg . The pH is measured and adjusted to pH 7.1 by adding NaOH and concentrated HCl. This visually clear solution at pH 7.1 has a concentration of insulin glargine Cmsuiine glargine (U / mL) and a concentration of co-polyamino acid Co-poiyaminoadde (mg / mL) = Diluted ceopolyamino acid (mg / mL) X Cinsulin glargine (U / mL) / 50 (U / mL).

According to this CA2 preparation process, copolyamino acid / insulin glargine compositions were prepared for example with insulin glargine concentrations of 200 U / ml and 400 U / ml at pH 7.1.

Example CA3: Preparation of co-polyamino acid / insulin glargine 200 U / ml compositions at pH 7.1.

[000590] Co-polyamino acid / insulin glargine 200 U / ml compositions are prepared according to the method described in Example CA2 so as to obtain a concentration of insulin glargine Cinsulin glargine = 200 U / ml and a concentration of co-polyamino acid Cco -polyamino acid (mg / mL).

These compositions are presented in Table 3.

114

compositio not Copolyaminoacid e Copolyamino acid concentration (mg / ml) Insulin glargine (U / mL) CA3-1 B3 5 200 CA3-2 B4 7 200 CA3-4 B5 10 200 CA3-5 B6 5 200 CA3-6 B7 5 200 CA3-8 BII 6 200 CA3-9 B14 7 200

Table 3: Insulin glargine compositions (200 U / mL) in the presence of copolyamino acid.

Eartie Cg - Compositions including deTinsyline glargine et.d.e Hnsqline lisoro

Preparation process CB1: Preparation of a diluted copolyamino acid / insulin glargine composition 43 U / mL / insulin lispro 13.5 U / mL [000591] At a diluted Vco-polyamino acid / insulin glargine volume of the diluted co-polyamino acid / insulin composition glargine 50 U / mL at pH 7.1 described in the CAI example is added a Vinsulin lispro volume of a commercial solution of insulin lispro Humalog® at 100 U / mL and water so as to obtain a co -polyamino acid / insulin glargine 43 (U / mL) / insulin lispro 13.5 (U / mL).

Preparation process CB2: Preparation of a copolyamino acid / insulin glargine / insulin lispro composition concentrated at pH 7.1 [000592] A co-polyamino acid / insulin glargine 43 (U / mL) / insulin lispro 13.5 (U / mL) composition ) described in Example CB1 is concentrated by ultrafiltration on a 3 kDa regenerated cellulose membrane (Amicon® Ultra-15 sold by the company Millipore). At the end of this ultrafiltration step, the retentate is clear and the insulin glargine concentration in the composition is determined by reverse phase chromatography (RP-HPLC). The insulin glargine and insulin lispro concentrations in the composition are then adjusted to the desired value by dilution in a solution of m-cresol / glycerin excipients so as to obtain a final m-cresol concentration of 35 mM and an osmolarity of 300 mOsm / kg. The pH is measured and adjusted if necessary to pH 7.1 by adding NaOH and

115

HCI concentrated. This visually clear solution at pH 7.1 has a concentration of insulin glargine Cinsuiine giargine (U / mL), a concentration of insulin lispro Cinsuiine iispro ⁼ Cinsuiine giargine x 0.33 and a concentration of co-polyamino acid

Co-polyaminoadde (mg / mL) = Diluted co-polyamino acid (mg / mL) X Cinsuiine giargine (U / mL) / 50 5 (U / mL).

Example CB3: Preparation of co-polyamino acid / insulin giargine 200 U / ml / insulin iispro 66 U / ml compositions at pH 7.1 [000593] Co-polyamino acid / insulin giargine 200 U / ml / insulin 10 iispro 66 U / compositions mL are prepared according to the process described in Example CB2 so as to obtain a concentration of insulin giargine Cinsuiine giargine - 200 U / mL, a concentration of insuiine lispro Cinsuiine iispro = 66 U / mL and a concentration of copolyamino acid Cco-polyaminoadde ( mg / mL).

These compositions are presented in Table 4.

Composition Co- polyamino Copolyamino acid concentration (in mq / ml) Insulin giargine U / ml Insulin lispro U / ml CB3-1 B1 17 200 66 CB3-2 B4 5 200 66 CB3-3 B3 7 200 66 CB3-4 8 200 66 CB3-6 B5 10 200 66 CB3-7 B6 5 200 66 CB3-8 B7 5 200 66 CB3-10 BII 6 200 66 CB3-11 B12 8 200 66 CB3-12 B14 7 200 66

Table 4: Compositions of insulin giargine (200 U / mL) and insulin lispro (66 U / mL) in the presence of co-polyamino acid.

116

Pgjrtiç p - Results

Physical stability of compositions prepared above

Example PI: Accelerated stability at 25 ° C in dynamics.

3 vials of 3 mL filled with 1 mL of co-polyamino acid / insulin glargine or co-polyamino acid / insulin glargine / prandial insulin composition are placed vertically on an orbital shaker. The agitator is placed in an oven at 25 ° C. and the vials are subjected to agitation of 50 or 250 rpm. The vials are visually inspected daily / weekly to detect the appearance of visible particles or turbidity. This inspection is carried out according to the recommendations of the European Pharmacopoeia (EP 2.9.20): the vials are subjected to lighting of at least 2000 Lux and are observed in front of a white background and a black background. The number of days of stability corresponds to the time from which at least 2 vials have visible particles or are turbid.

The results of accelerated stability (obtained with different compositions) are presented in Table 5, Table 6.

Composition Co- polyamino concentration (Mg / mL) Stability in days CA3 : * CA3-1 B4 5 > 24 CA3-2 B3 7 > 24 CA3-5 B6 5 > 24 CA3-6 B7 5 > 24 CA3-8 BII 6 > 24

Table 5: results of the stabilities of the co-polyamino acid / insulin glargine compositions (200 U / ml) at 25 ° C. under dynamic conditions (with stirring at 250 rpm). (* Appearance of a precipitate when the pH of the insulin glargine solution is adjusted to pH 7).

117

cOMPOSITIO not Co- polyamino Concentration (mg / mL) Stability in days CB3 "· J. ; * CB3-1 BI 17 > 10 CB3-2 B4 5 > 20 CB3-3 B3 7 > 20 CB3-4 8 > 20 CB3-6 B5 10 > 20 CB3-7 B6 5 > 20 CB3-8 B7 5 > 20 CB3-12 B9 6 > 20 CB3-10 BII 6 > 20 CB3-11 B12 8 > 20

Table 6: results of the stability of the co-polyamino acid / insulin glargine (200 U / mL) / insulin lispro (66 U / mL) compositions at 25 ° C. under dynamic conditions (with stirring at 250 rpm). (* Appearance of a precipitate when the pH of the insulin glargine solution is adjusted to pH 7).

The compositions according to the invention with insulin glargine and with insulin glargine and insulin lispro have good dynamic stability

Example D2: Accelerated stability at 30 ° C in static mode [000597] 5 vials of 3 ml filled with 1 ml of composition are placed vertically in an oven maintained at 30 ° C. The vials are visually inspected daily to detect the appearance of visible particles or turbidity. This inspection is carried out in accordance with the recommendations 15 of the European Pharmacopoeia (EP 2.9.20): the vials are subjected to lighting of at least 2000 Lux and are observed in front of a white background and a black background. The number of weeks of stability corresponds to the time from which at least half of the vials have visible particles or are turbid.

These results are in agreement with the US Pharmacopoeia (USP <790>).

The results of accelerated stability (obtained with different compositions are presented in Tables 8a and 8b below.

118

compositions Co- polyamino Stability at 30 ° C static (weekdays) CA3 - * CA3-2 B4 > 16 CA3-1 B3 > 19 CA3-9 B14 > 19 CA3-4 B5 > 19 CA3-5 B6 > 19 CA3-6 B7 > 18 CA3-8 BII > 19

Table 8a: results of the stability of the copolyamino acid / insulin glargine compositions (200 U / ml) at 30 ° C in static. (* Appearance of a precipitate when the pH of the solution is adjusted to pH 7).

Composition Co- polyamino Stability at 30 ° C static (weekdays) CB3 * CB3-1 bl > 16 CB3-2 B4 > 16 CB3-4 83 (8) > 16 CB3-12 B14 > 16 CB3-6 B5 > 16 CB3-7 B6 > 16 CB3-8 B7 > 16 CB3-10 BII > 16 CB3-11 B12 > 16

Table 8b: results of the stabilities of the co-polyamino acid / insulin glargine (200 U / mL) / insulin lispro (66 IU / mL) compositions at 30 ° C in static. (* Appearance of a precipitate when the pH of the solution is adjusted to pH 7).

The compositions according to the invention with insulin glargine and with insulin glargine and insulin lispro have good static stability at 30 ° C.

Example D3: Accelerated stability at 40 ° C in static [000602] The accelerated stability at 40 ° C in static of the compositions was also analyzed according to the same protocol as in Example D2.

These results are in agreement with the US Pharmacopoeia (USP <790>).

The results of accelerated stability (obtained with different compositions are presented in Table 8c below.

119

Composition Co- polyamino Stability at 40 ° C static (in week) CB3 : * CB3-2 B3 > 3 CB3-4 B4 (8) > 3

Table 8c: results of the stability of the co-polyamino acid / insulin glargine (200 U / mL) / insulin lispro (66 IU / mL) compositions at 40 ° C. in static. (* Appearance of a precipitate when the pH of the solution is adjusted to pH 7).

The compositions according to the invention with insulin glargine and insulin lispro have good static stability at 40 ° C.

Example D3: Precipitation of insulin glargine in copolyamino acid / insulin glargine compositions at 200 U / ml [000606] 1 ml of co-polyamino acid / insulin glargine solution prepared in Example CA3 is added to 2 ml of a solution PBS (Phosphate Buffer Saline, phosphate buffered saline) containing 20 mg / mL of BSA ((Bovine serum albumin, bovine serum albumin)). The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears.

[000607] Centrifugation at 4000 rpm is carried out to separate the precipitate from the supernatant. Then insulin glargine is assayed in the supernatant by RP-HPLC. As a result, insulin glargine is mainly found in a precipitated form.

The results are presented in Table 7.

compositi we Co- polyaminoac ide Insuli don't widen don't Concentration in copolyaminoac ide (in mg / ml) Insulin glargine solubilization Precipitate! wave insulin glargine 200 · NO N / A CA3-1 B4 200 5 YES YES CA3-2 B3 200 7 YES YES CA3-4 B5 200 10 YES YES CA3-5 B6 200 5 YES YES CA3-9 B14 200 7 YES YES

Table 7: Co-polyamino acid / insulin glargine compositions (200 U / mL); solubilization / precipitation of insulin glargine.

120 [000608] The co-polyamino acids make it possible to prepare an insulin glargine solution at neutral pH and allow precipitation thereof when said solution is added in a medium simulating the subcutaneous medium.

Example D4: Precipitation of insulin glargine in the copolyamino acid / insulin glargine 200 U / mL / insulin lispro 66 U / mL at pH 7.1 [000609] 1 mL of co-polyamino acid / insulin glargine / insulin lispro solution prepared in example CB3 is added in 2 mL of a PBS solution containing 20 mg / mL of BSA (bovine serum albumin). The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears.

[000610] Centrifugation at 4000 rpm is carried out to separate the precipitate from the supernatant. Then insulin glargine is assayed in the supernatant by RP-HPLC. As a result, insulin glargine is mainly found in a precipitated form. The results are presented in Table 8.

Compositions Copolyamino acid Insuli don't widen don't Lisp ro Acid copolyamino concentration (mg / ml) Insulin glargine solubilization Insulin glargine precipitation CB3-1 bl 200 66 17 YES YES CB3-2 B4 200 66 5 YES YES CB3-3 B3 200 66 7 YES YES CB3-6 B5 200 66 10 YES YES CB3-7 B6 BC422 200 66 5 YES YES CB3-12 BB14 200 66 7 YES YES CB3-8 B7 200 66 5 YES YES CB3-10 BII 200 66 6 YES YES CB3-11 B12 200 66 8 YES YES CB3-9 B13 200 66 5 YES YES

Table 8: Co-polyamino acid / insulin glargine (200 U / mL) / insulin lispro (66 U / mL) compositions; solubilization and precipitation of insulin glargine.

The co-polyamino acids make it possible to prepare a solution of insulin glargine in the presence of insulin lispro at neutral pH and allow precipitation of

121 insulin glargine when said solution is added in a medium simulating the subcutaneous medium.

£ xem & lË-P5 „: ..... Pharmacodynamics chezjeçh.i £ B [000612] Studies in dogs have been carried out with the objective of evaluating the pharmacodynamics of insulin after administration of the composition of copolyamino acid Bll and insulins (composition CB3-10).

The hypoglycemic effects of this composition have been compared with those of simultaneous but separate injections of Lantus® (pH 4) and Humalog® in the proportions 75% of Lantus® / 25% of Humalog® ( dose / dose).

Ten animals, which have been fasted for approximately 18 h, were injected at the neck, above the interscapular region, at a dose of 0.67 U / kg. In the hour before the injection, 3 samples are taken to determine the basal glucose level. The blood sugar is then determined for 24 h using a glucometer.

The mean pharmacodynamic curves of glucose expressed in percent deviations from the basal level are shown in FIG. 1.

The pharmacodynamic results obtained with the simultaneous and separate administrations of Humalog® (example Cl) and Lantus® (example C4) in comparison with the composition CB3-10 are presented in Figure 1. The hypoglycaemic activity of the composition CB3-10 is biphasic. The first rapid phase is defined by a marked decrease in blood sugar for approximately 60 minutes characteristic of the rapid effect of insulin lispro. This first phase is also visible on the Lantus® / Humalog® double injection, indicating that the invention does not modify the rapidity of Humalog®. After about 60 minutes, the blood sugar rises up to 3 h before a second slower phase, characterized by less marked hypoglycaemic activity and prolonged until 18-20 h post-injection. This second basal phase is characteristic of the basal effect of insulin glargine, also visible on the double injection, indicating that this basal effect is well preserved with the composition CB3-10.

Claims (27)

1. Physically stable composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least: a) a basal insulin whose isoelectric point (pi) is between 5.8 and 8.5 and b) a co-polyamino acid of formula I QtHyMPLGh Formula I In which : j> 1; k> 2 said co-polyamino acid of formula I carrying carboxylate charges and consisting of at least two chains of PLG glutamic or aspartic units linked together by a radical or spacer Q [- *] i (i> 3 with i = j + k) linear or branched at least trivalent consisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen atoms and oxygen and / or radicals carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions, said radical Q [- *], carrying at least one monovalent hydrophobic radical —Hy; - said radical or spacer Q [- *], being linked to at least two chains of glutamic or aspartic units PLG by an amide function and, - Said radical or spacer Q [- *], being linked to at least one hydrophobic radical —Hy of formula X below defined by an amide function. 2. Composition according to claim 1, characterized in that the radical or spacer Q [- *] i (i> 3) is represented by a radical of formula II: QL - *] i - ([Q '] q) [“* li Formula II In which 1 <q <5 The radicals Q 'being identical or different and chosen from the group consisting of the radicals of formulas III to VI below, to form Q [- *] i (i> 3) 123 * ^F a ---- F _a . * * Formula III Where 1 <t <8 Formula IV In which : At least one of the ui or U2 is different from 0. If ui * 0 then ui '* 0 and if U2 * 0 then U2' * 0, uf and U2 'are identical or different and, 2 <u <4, 0 <ui '<4, 0 <ui <4, 0 <U2 '<4 0 <U2 <4 and, In which : v, v 'and v identical or different, v + v' + v <15 Formula VI In which : wi 'is different from 0, 0 <W ₂ <1, wi <6 and wf <6 and / or W2 <6 and W2 ^Z <6 with Fx = Fa, Fb, Fc, Fd, Fa ', Fb', Fc ', Fc and Fd' identical or different representing functions -NH- or -CO- and Fy representing a trivalent nitrogen atom -N =, 124 two radicals Q ′ being linked together by a covalent bond between a carbonyl function, Fx = -CO-, and an amine function Fx = -NH- or Fy = -N =, thus forming an amide bond, 3. Composition according to any one of the preceding claims, characterized in that the hydrophobic radical --Hy is chosen from the radicals of formula X as defined below: * - ^ GpR ^ -— ^ GpG ^ - (GpA) - (GpL ^ - (GpHj-— GpC ^a Formula X in which: - GpR is chosen from the radicals of formulas VII, VU 'or VU: HH? H * N — R — N * _Formu | _{e VII 0 (J} * R —- N * Formula VII'or O O * —U-R-U— * Form VU; Identical or different GpG and GpH are chosen from the radicals of formulas XI or ΧΓ: O. Il _n ! J "* --- NH --- G --- NH --- * ^N Formula XI Formula XI ' GpA is chosen from the radicals of formula VIII * - NH— 1 ’- [NH— | * * Formula VIII In which A 'is chosen from the radicals of formula VIII', VIII or HIV ' Formula VIII ' Formula VIII Formula VIII ' -GpL is chosen from the radicals of formula XII 125 Ο ΗΝ— * • -La '% ΗΝ— * Formula XII, GpC is a radical of formula IX: Formula IX; - the * indicate the sites of attachment of the different groups linked by amide functions; - a is an integer equal to 0 or 1 and a '= 1 if a = 0 and a' = 1, 2 or 3 if a = 1; - a 'is an integer equal to 1, 2 or 3 b is an integer equal to 0 or 1; - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2; - d is an integer equal to 0, 1 or 2; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3 to 4 to 5 or 6; - h is an integer equal to 0, 1, 2, 3 to 4 to 5 or 6; I is an integer equal to 0 or 1 and 1 '= 1 if I = 0 and Γ = 2 if I = 1; r is an integer equal to 0 or 1, and s' is an integer equal to 0 or 1; - A, Ai, A2 and A3, which are identical or different, are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms; - B is 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, in which x indicates the number of carbon atoms and: • When the hydrophobic radical -Hy carries 1 -GpC, then 9 <x <25, When the hydrophobic radical -Hy carries 2 -GpC, then 9 <x <15, When the hydrophobic radical -Hy carries 3 -GpC, then 7 <x <13, • When the hydrophobic radical -Hy carries 4 -GpC, then 7 <x <11, • When the hydrophobic radical -Hy carries at least 5 -GpC then, 6 <x < 11 126 - G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s). - H is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s)., - 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: - The hydrophobic radical (s) -Hy of formula X being linked to Q: o via a covaited bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by Q thus forming an amide function resulting from the reaction of an amine function carried by the precursor of Q and an acid function carried by the precursor -Hy 'of the hydrophobic radical -Hy, and o via a covalent bond between a nitrogen atom of the hydrophobic radical -Hy and a carbonyl carried by Q, thus forming an amide function resulting from the reaction of an amine function of the precursor - Hy 'of the hydrophobic radical -Hy and an acid function carried by the precursor of the radical Q, the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <M <0.5; - When several hydrophobic radicals are carried by a co-polyamino acid then they are identical or different, ie degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250; the free carboxylic acid functions being in the form of an alkali cation salt chosen from the group consisting of Na ⁺ and K ⁺ . 4. Composition according to any one of the preceding claims, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula 127 Next XXXa: in which, • D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • X represents a cationic entity chosen from the group comprising the alkali cations, • Ra and Ra ', identical or different, are 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 , • Q, Hy and j have the meanings given above. • 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 co-polyamino acid and 5 <n + m <250. Composition according to the preceding claim, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'below: 128 Formula XXXa '• D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • X represents a cationic entity chosen from the group comprising alkaline cations, • Q, Hy and j have the meanings given above. • Ra and Ra ', identical or different, are a radical chosen from the group consisting of an H, a linear acyl group at C2 to CIO, a branched acyl group at C3 to CIO, a benzyl, a terminal "amino acid" unit and a pyroglutamate, • ni + mi represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid carrying a radical -Hy • n ₂ + m2 represents the number of glutamic units or aspartic units of the PLG chains of co -polyamino acid not carrying a radical -Hy • ni + n2 = n and mi + m ₂ = m • n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of units monomers per co-polyamino acid chain and 5 <n + m <250; Composition according to the preceding claim, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa below: Formula XXXa 129 • D represents, independently, either a group -CH ₂ - (aspartic unit) or a group -CH ₂ -CH ₂ - (glutamic unit), • Ri represents a radical or spacer of formula Q [- *] i such that previously defined, • X represents a cationic entity chosen from the group comprising the alkaline cations, • Q, Hy and j have the meanings given above, • R _a and Ra ', identical or different, are at least one hydrophobic radical - Hy and a radical chosen from the group consisting of -Hy, an H, a linear acyl group at C2 to CIO, a branched acyl group at C3 to CIO, a benzyl, a terminal "amino acid" unit and a pyroglutamate, • 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 co-polyamino acid and 5 <n + m <250. Composition according to Claim 4, characterized in that the copolyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb below: in which, • D represents, independently, either a group -CH ₂ - (aspartic unit) or a group -CH2-CH2- (glutamic unit), • R2 represents a radical or spacer of formula Q [- *] i such that previously defined, • X represents a cationic entity chosen from the group comprising the alkaline cations, • Rb and Rb ', identical or different, are a radical -NR'R, R' and R identical or different being chosen from the group consisting of H 130 linear or branched or cyclic C2 to CIO alkyls, 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 by O, N and S; • Q, Hy and j have the meanings given above. "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 co-polyamino acid and 5 <n + m <250. Composition according to Claim 6, characterized in that the copolyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'below: independently represents either a Formula XXXb 'group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • R2 represents a radical or spacer of formula Q [- *] r as defined above, • X represents a cationic entity chosen from the group comprising the alkaline cations, • Q, Hy and j have the meanings given above. • Rb and Rb ', identical or different, are a radical -NR'R, R' and R identical or different being selected from the group consisting of H, linear or branched or cyclic C2 to C10 alkyl, benzyl and said R ′ and R alkyl 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; 131 • nl + ml represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid carrying a radical -Hy, • n2 + m2 represents the number of glutamic units or units 5 aspartics of the PLG chains of the co-polyamino acid not carrying a radical -Hy • nl + n2 = n and ml + m2 = m, • n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say say the average number of monomeric units per chain of 10 co-polyamino acid and 5 <n + m <250; Composition according to claim 6, characterized in that the copolyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb below: Formula XXXb • D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • R2 represents a radical or spacer of formula Q [- *] i such that 20 previously defined, • X represents a cationic entity chosen from the group comprising the alkaline cations, • Rb and Rb ', identical or different, are at least one hydrophobic radical -Hy and a radical chosen from the group consisting of a radical Hydrophobic -Hy and an identical or different radical -NR'R, R 'and R being chosen from the group consisting of H, linear or branched C2 or C10 cyclic alkyls, benzyl and said R' and R alkyls which may 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; 132 • Q, Hy and j have the meanings given above. • 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 co-polyamino acid and 5 <n + m <250; 5. Composition according to any one of the preceding claims, characterized in that the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine 6. Composition according to any one of the preceding claims, characterized in that it comprises between 40 and 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5. 7. 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 60 mg / ml. 8. Composition according to any one of the preceding claims, characterized in that the concentration of charge-carrying co-polyamino acid 20 carboxylates and hydrophobic radicals is at most 40 mg / mL. 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 20 mg / ml. 10. 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 10 mg / ml. 30 11. Composition according to any one of the preceding claims, characterized in that it further comprises a mealtime insulin. 12. Composition according to the preceding claim, characterized in that the meal insulin is human insulin. 13. Composition according to any one of claims 19 and 20, characterized in that in total it comprises between 40 and 500 U / ml of insulin with 133 a combination of mealtime insulin and basal insulin with an isoelectric point between 5.8 and 8.5. 14. Composition according to any one of claims 19 to 21, characterized in that the proportions between the basal insulin whose isoelectric point is between 5.8 and 8.5 and the mealtime insulin are in percentage of 25 / 75, 30/70, 40/60, 50/50, 60/40, 70/30, 80/20 or 90/10. 15. Composition according to any one of the preceding claims, characterized in that it also comprises a gastrointestinal hormone. 16. Composition according to the preceding claim, 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. 17. Composition according to any one of claims 23 to 24, characterized in that the gastrointestinal hormone is dulaglutide, its analogs or derivatives and their pharmaceutically acceptable salts. 18. Composition according to any one of claims 23 to 24, characterized in that the gastrointestinal hormone is exenatide, its analogs or derivatives and their pharmaceutically acceptable salts. 19. Composition according to any one of claims 23 to 24, characterized in that the gastrointestinal hormone is liraglutide, its analogs or derivatives and their pharmaceutically acceptable salts. 20. Composition according to any one of claims 23 to 24, characterized in that the gastrointestinal hormone is lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts. 21. Composition according to any one of claims 23 to 28, characterized in that the concentration of gastrointestinal hormone is in the range of 0.01 to 10 mg / ml. 134 22. Composition according to any one of claims 24 or 26, characterized in that it comprises between 40 U / ml and 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and 0.05 to 0.5 mg / mL exenatide. 23. Composition according to any one of claims 24 or 27 characterized in that it comprises between 40 U / ml and 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and 1 to 10 mg / mL of liraglutide. 24. Composition according to any one of claims 24 or 28, characterized in that it comprises between 40 U / ml and 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide. 25. Single-dose formulation at pH between 7 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin. 26. Single-dose formulation at pH between 7 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone. 27. Single-dose formulation at pH between 7 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone.