WO2019243628A1

WO2019243628A1 - Injectable composition with a ph of 7 comprising a co-polyaminoacid bearing carboxylate charges and hydrophobic radicals and at least one basal insulin having at least a prandial effect and a basal effect

Info

Publication number: WO2019243628A1
Application number: PCT/EP2019/066614
Authority: WO
Inventors: Martin Gaudier
Original assignee: Adocia
Priority date: 2018-06-22
Filing date: 2019-06-24
Publication date: 2019-12-26

Abstract

A 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 of which the isoelectric point pI is between 5.8 and 8.5; and b) a co-polyaminoacid bearing carboxylate charges and hydrophobic radicals Hy, in a method for treating diabetes and controlling blood glucose, characterised in that the basal insulin has a prandial effect and a basal effect.

Description

PH 7 INJECTION COMPOSITION COMPRISING A CO-POLYAMINOACID CARRYING CARBOXYLATES AND HYDROPHOBIC RADICALS AND AT LEAST ONE BASAL INSULIN HAVING AT LEAST ONE PRANDIAL EFFECT AND A BASAL EFFECT

The invention relates to insulin injection therapy (s) for treating diabetes.

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 allow to 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 ADOs 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, insulin degludec or insulin detemir in addition to the OADs, then then depending on the evolution of the pathology a treatment based on basal insulin and meal insulin.

[0004] Furthermore, today, to ensure the transition from OAD treatments, when these are no longer able to control the level of glucose in the blood, towards a basal insulin / mealtime insulin treatment, the GLP-1 RA injection is recommended.

GLP-1 RA for Glucagon-Like Peptide-1 receptor agonists, 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.

[0006] The gastrointestinal hormones (Gut hormones) are also called satiety hormones. They include in particular GLP-1 RA (Glucagon like peptide- 1 receptor agonist), GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon), peptide YY, 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, the GLP-1 RA are those which have brought to date the best results in drug development. They have allowed patients with type II diabetes to lose weight while having better control of their blood sugar.

GLP-1 RAs 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 (metabolism 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 used meal insulins are: recombinant human insulin, NovoLog ^® (insulin aspart from NOVO NORDISK), Humalog ^® (insulin lispro from ELI LILLY) and Apidra ^® (insulin glulisine from 5ANOFI).

Basal insulins maintain the patient's glycemic homeostasis, outside of periods of food intake. They mainly act to block endogenous glucose production (hepatic glucose). The daily dose of basal insulin 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 (NPH insulin for Neutral

Protamine 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, protamine. The microcrystals thus formed are dispersed in an aqueous suspension and dissolve slowly after subcutaneous injection. This slow dissolution ensures a sustained 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 16 hours. It is therefore injected twice a day. This NPH basal insulin is much less effective 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 ^® (OVO NORDISK) 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 which remains soluble, the action of which is rapid. These formulations offer the advantage of a fast insulin but they also have the defect of IM PH, c. -to-d. 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 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 of 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 substitution of GA21 was thought in order to make insulin glargine stable at acidic pH and thus to be able to formulate it in the form of a solution for injection at acidic pH.

The addition of two arginine residues has been 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. 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 insulin glargine microparticles ensures slow and prolonged 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 acid 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 acid pH of the formulation of insulin glargine sometimes causes pain in injection patients and especially prevents any formulation with other proteins and in particular with meal insulin because the latter are not stable at acid pH. The impossibility of formulating a prandial insulin at acid pH is due to 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 injectable medicaments.

The glycemic variability corresponds to the glycemic fluctuations during the day. It now seems established that the alternation of hypoglycaemia and hyperglycaemia can have a harmful effect, such as the development of complications.

A good marker of blood sugar in diabetics is the difference observed between postprandial blood sugar and fasting blood sugar. This is what is called "post-prandial glycemic excursion" or "post-prandial increment" also called "post-prandial delta".

There is a significant need for patients treated with combinations of basal and prandial insulins, to limit these post-prandial glycemic excursions.

Furthermore, it is known in particular from E. Cengiz, Diabetes Care 2010, ppl009-1012, that there is a risk of slowing down the effect of the prandial insulins formulated at neutral pH when they are mixed with formulated basal insulins. at acidic pH.

Surprisingly, the applicant has demonstrated that compositions comprising basal insulin and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical made it possible to obtain both a basal effect and a mealtime effect from basal insulin.

These compositions can limit the number and / or the extent of postprandial hypoglycaemia, or even eliminate them, and limit the glycemic variability.

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 carrying carboxylate charges and at least one hydrophobic radical of formula X,

for use in a method of treating diabetes and controlling blood sugar, characterized in that the basal insulin has a prandial effect and a basal effect.

In one embodiment, the invention relates to a 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) meal insulin, and

c) a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula X,

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

b) a gastrointestinal hormone, and

c) a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula X, for use in a method of treating diabetes and controlling blood sugar, characterized in that the basal insulin has a prandial effect and a basal effect.

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

b) meal insulin and gastrointestinal hormone, and

In one embodiment, the invention relates to the use of a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula X to confer a prandial effect on a basal insulin whose isoelectric point (pi) is between 5.8 and 8.5.

By basal effect is meant the observation of a plateau or pseudo-plateau of the plasma concentration in humans, of basal insulin, said plateau corresponding to a plasma concentration of basal insulin, constant or with slight variations. concentration 6 h after administration and for at least 12 h after administration of the formulation.

In one embodiment, said plateau or pseudo-plateau is observed from 6 to 18 h after the administration of the formulation.

In one embodiment, said plateau or pseudo-plateau is observed from 6 to 20 h after administration of the formulation

The prandial effect can be characterized by the observation of a marked peak in the plasma concentration, in humans of basal insulin, said peak being observed at the latest between 0 and 6 h following the administration of the formulation.

In one embodiment, this peak corresponds to a large and rapid rise in the plasma insulin concentration. In one embodiment, this peak is observed at the latest between 0 and 5 hours following the administration of the formulation. In one embodiment, this peak is observed at the latest between 0 and 4 hours following the administration of the formulation.

In one embodiment, this peak is observed at the latest between 0 and 3 hours following the administration of the formulation.

In one embodiment, this peak is observed at the latest between 0 and 2 hours following the administration of the formulation.

In one embodiment, this peak is observed at the latest between 0 and 1 hour following the administration of the formulation.

In one embodiment, this peak is observed at the latest between 0 and 0.5 h following the administration of the formulation.

In a particular embodiment, the composition according to the invention leads to a prandial effect originating from basal insulin characterized by a marked peak in basal insulin within 0-4 hours after administration.

In a particular embodiment, the composition according to the invention results in a prandial effect originating from basal insulin characterized by a marked peak in basal insulin within 0-3 hours after administration.

In a particular embodiment, the composition according to the invention leads to a prandial effect originating from basal insulin characterized by a marked peak in basal insulin within 0-2 hours after administration.

In a particular embodiment, the composition according to the invention leads to a prandial effect originating from basal insulin characterized by a marked peak in basal insulin within 0-1 h after administration.

In the case of Lantus ^® or Toujeo ^® , such a peak is not observed in humans.

Composition according to the invention, characterized in that the onset of the meal effect is obtained within a period of between 0 and 30 minutes after administration.

The prandial effect originating from basal insulin can also be characterized by an area under the curve of the concentration of basal insulin at early times, for example between 0 and 30 minutes, 0 and 60 minutes or even 0 and 120 minutes.

According to one embodiment the prandial effect originating from basal insulin is characterized by an area under the curve of the basal insulin concentration between 0 and 30 min (AUCbas0-30) greater than an identical composition devoid of co - charge carrier polyamino carboxylates and hydrophobic radicals Hy or a composition of Lantus ^®. According to one embodiment, the prandial effect originating from basal insulin is characterized by an area under the curve of the basal insulin concentration between 0 and 60 min (AUCbas0-60) greater than an identical composition devoid of co - charge carrier polyamino carboxylates and hydrophobic radicals Hy or a composition of Lantus ^®.

According to one embodiment the prandial effect originating from basal insulin is characterized by an area under the curve of the basal insulin concentration between 0 and 120 min (AUCbasO-120) greater than an identical composition devoid of co - charge carrier polyamino carboxylates and hydrophobic radicals Hy or a composition of Lantus ^®.

In one embodiment, the composition according to the invention is characterized in that the basal effect is preserved within a period of between 15 minutes and at least 12 hours after administration.

In one embodiment, the composition according to the invention is characterized in that the basal effect is preserved within a period of between 15 minutes and at least 16 hours after administration

In one embodiment, the composition according to the invention is characterized in that the basal effect is preserved within a period of between 15 minutes and at least 18 hours after administration

In one embodiment, the composition according to the invention is characterized in that the basal effect is preserved within a period of between 15 minutes and at least 24 hours after administration

In one embodiment, the composition according to the invention is characterized in that it is administered 1 time per day.

In one embodiment, the composition according to the invention is characterized in that it is administered at least 2 times a day.

In one embodiment, the composition according to the invention is characterized in that it is administered 2 times a day.

In one embodiment, the composition according to the invention is characterized in that it further comprises a mealtime insulin.

In one embodiment, the composition according to the invention further comprising at least one mealtime insulin is characterized in that it is administered 1 time per day.

In one embodiment, the composition according to the invention further comprising at least one prandial insulin is characterized in that it is administered at least 2 times a day. In one embodiment, the composition according to the invention further comprising at least one meal insulin is characterized in that it is administered twice a day.

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

In one embodiment, the composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered 1 time per day.

In one embodiment, the composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered at least 2 times a day.

In one embodiment, the composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered 2 times a day.

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

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

In one embodiment, the composition according to the invention further comprising at least one GLP-1 RA is characterized in that it is administered at least 2 times a day.

In one embodiment, the composition according to the invention further comprising at least one GLP-1 RA is characterized in that it is administered 2 times a day.

In one embodiment, said co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, consists of glutamic or aspartic units and said hydrophobic Hy radicals are radicals of the following formula X:

Formula X in which GpR is chosen from the radicals of formulas VII, VIF or VII ":

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

,,

Formula XI

- GpA is chosen from the radicals of formula VIII

Formula VIII

In which A 'is chosen from the radicals of formula HIV', VIII "or HIV '

Form VIII 'Form VIII "Form VIII"

-GpL is chosen from the radicals of formula XII

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;

s' is an integer equal to 0 or 1, and

A, Ai, A2 and A3, which are identical or different, are linear or branched alkyl radicals, and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring, comprising from 1 to 8 carbon atoms;

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

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

■ 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).

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 the PLG:

o via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by the PLG thus forming an amide function derived of the reaction of an amine function carried by the PLG 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 PLG 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 PLG, 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 ⁺ .

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

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 hydrophobic radicals Hy is soluble in aqueous solution at pH between 6.0 and 8.0, at a temperature of 25 ° C and at a concentration of less than 100 mg / ml .

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

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

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

The term “physically stable composition” is understood to mean compositions which satisfy 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 solution for injection" means solutions in which the solvent is water and which satisfy the conditions of the EP and US pharmacopoeias.

The compositions in the form of an injectable aqueous solution according to the invention are clear solutions. The term “clear solution” is understood to mean compositions which satisfy the criteria described in the American pharmacopoeias and European standard for injectable solutions. In the US Pharmacopoeia, the solutions are defined in the section <1151> referring to the injection <1> (referring to <788> according to USP 35 and specified in <788> according to USP 35 and in <787>, <788> and <790> USP 38 (from ¹ August 2014), according to USP 38). In the European Pharmacopoeia, injectable solutions must meet the criteria given in sections 2.9.19 and 2.9.20.

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 allow a clear solution free of particles to be prepared at a concentration of less than 100 mg / ml in distilled water at 25 ° C.

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

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

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

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

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms.

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

In the formulas, the * indicate the sites of attachment of hydrophobic radicals to P LG or between the different groups GpR, GpG, GpH, GpA, GpL and GpC to form amide functions.

The Hy radicals are attached to the PLG via amide functions.

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

In one embodiment, r = 1 or 2 and the hydrophobic radical of formula X is linked to the PLG:

* via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl carried by the PLG, 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 PLG or,

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

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

the GpCs are linked directly or indirectly to N _ai and N and the PLG is linked directly or indirectly via GpR to Nri, or

the GpCs are linked directly or indirectly to N „i and Npi, and the PLG is linked directly or indirectly via GpR to N _t , or

the GpCs are linked directly or indirectly to _a2 and Npi, and the PLG is linked directly or indirectly via GpR to N _ai .

In one embodiment, if GpA is a radical of formula City and r = 0, then:

the GpC are linked directly or indirectly to (May and N _a2 and the PLG is linked directly or indirectly to Npi; or

the GpCs are linked directly or indirectly to N _ai and Npi, and the PLG is linked directly or indirectly to N _a2 ; or

the GpCs are linked directly or indirectly to N and Npi, and the PLG is linked directly or indirectly to N _ai .

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

the GpCs are linked directly or indirectly to N "i, N _a2 and IMpi and the PLG is linked directly or indirectly via GpR to Np ₂ ; or

the GpCs are linked directly or indirectly to IN, N and N _b2 and the PLG is linked directly or indirectly via GpR to Npi; or the GpCs are linked directly or indirectly to N "i, Npi and Np ₂ and the PLG is linked directly or indirectly via GpR to N; or

the GpCs are linked directly or indirectly to N ', Npi and Np ₂ and the PLG is linked directly or indirectly via GpR to N _ai .

In one embodiment, if GpA is a radical of formula VUId and r = 0, then

the GpCs are linked directly or indirectly to N _a i, N _a2 and Npi and the PLG is linked directly or indirectly to Np ₂ ; or

- the GpCs are linked directly or indirectly to N _a i, N _a2 and Np ₂ and the PLG is linked directly or indirectly to IMpi; or

the GpCs are linked directly or indirectly to _p i, Npi and Np ₂ and the PLG is linked directly or indirectly to Na:; or

the GpCs are linked directly or indirectly to N _k2 , Npi and Np ₂ and the PLG is linked directly or indirectly to N "i _*

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

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

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

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

In one embodiment, a = 0,

In one embodiment h = 1 and g = 0,

In one embodiment h = 0 and g = l,

In one embodiment, r = 0, g = l and h = 0.

In one embodiment, at least one of the g, h or I is different from 0.

In one embodiment at least one of g and of h is equal to 1.

In one embodiment at least one of g and h is equal to 1.

In one embodiment a = 1 and I = 1.

In one embodiment, if I = 0, at least one of the g or h is equal to 0.

In one embodiment, if I = 1, at least one of the g or h is equal to 0.

In one embodiment g + h> 2.

In one embodiment g is greater than or equal to 2 (g> 2). In one embodiment h is greater than or equal to 2 (h> 2).

In one embodiment, g + h> 2 and a and I are equal to 0 (a = l = 0).

In one embodiment, g + h> 2 and b is equal to 0 (b = 0).

In one embodiment g or h is greater than or equal to 2 (g> 2) and b is equal to 0.

In one embodiment, g + h> 2, b is equal to 0 (b = 0) and e is equal to 1 (e = l).

In one embodiment g or h is greater than or equal to 2 (g> 2) b is equal to 0 (b = 0) and e is equal to 1 (e = l).

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

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

Formula VII

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

Formula Xc 'in which GpRi is a radical of formula VII

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

In one embodiment g = h = 0, a = 1, GpA is a radical of Formula VIII with s' = 1 and A 'of Formula VIII' or VIII ", and I = 1. In one embodiment, said at least one hydrophobic radical - Hy is chosen from the radicals of formula X in which r = 2 of formula Xc ', as defined below:

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

Formula VII

Formula Xc 'in which GpRi is a radical of formula VII ".

Formula VII "

In one embodiment, said at least one hydrophobic radical - Hy is chosen from the radicals of formula X in which

- I = o,

of formula Xb 'as defined below

Formula Xb 'in which

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

ormu e; GpG is chosen from the radicals of formula XI or XI ';

- NH - G - NH -

Formula XI Formula CI '

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:

H

HN- Villa Ai-N Formula - * VUIb Formula

GpC is a radical of formula IX:

a is an integer equal to 0 or 1 and a '= 1 if a = 0 and a' = 1 or a '= 2 if a = 1; a 'is an integer equal to 1 or 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 to 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 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, and at least one of the g or h is different from 0;

r is an integer equal to 0, 1 or 2, and

s' is an integer equal to 0 or 1; - Ai is a linear or branched alkyl radical, and optionally substituted by a radical resulting from a saturated, unsaturated or aromatic ring, 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 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;

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

* 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),

- 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 - COIMH2 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 the PLG:

via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by the PLG thus forming an amide function resulting from the reaction of an amine function carried by the PLG and an acid function carried by the precursor of the hydrophobic radical , and

o via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl carried by the PLG, 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 PLG.

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

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",

of formula Xb 'as defined below:

Formula Xb 'in which

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

ormu e;

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

* - _NH - G - NH - *

Formula XI Formula XV

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

* - N [it

\ A ^M s— N _a2 H— *

City Package

Formula VlIId;

GpC is a radical of formula IX

Formula IX; 21

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 or 3 if a = 1;

a 'is an integer equal to 2 or 3 and

5 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; 0 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;

5 r is an integer equal to 0, 1 or 2, and

s' is an integer equal to 1;

Ai, A2, A3 identical or different are linear or branched alkyl radicals, and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring, comprising from 1 to 6 carbon atoms;

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

^■ 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 <13.0 ^■ 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,

The hydrophobic radical (s) Hy of formula X being linked to the PLG: o via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by the PLG thus forming an amide function resulting from the reaction of a carried amine function by PLG 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 the PLG, 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 PLG.

G 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;

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

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:

Formula Xa in which GpA is a radical of formula VIII and A 'is chosen from the radicals of formula VIII' with s'-O and GpA is a radical of Formula VlIIb

O

_1L H

. D - *

^I Formula VlIIb

And GpR, GpG, GpL, GpH, GpC, Ai, 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 of formula Xb as defined below:

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

Villa formula

And GpR, GpG, GpL, GpH, GpC, Ai, a ', r, g, h, I and G 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:

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 Ville

City Package

And GpR, GpG, GpL, GpH, GpC, Ai, Ai, r, g, h, a ', I and have the definitions given above.

Formula Xb in which GpA is a radical of formula VIII and A is chosen from the radicals of formula HIV '"with s' = 1, and GpA is a radical of formula VUId

Formula VlIId; And GpR, GpG, GpL, GpH, GpC, Ai, Ai, A3, a ', r, g, h, I 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 hydrophobic radicals of formula X in which GpA is a radical of formula VlIIb, a '= 1 and I = 0 represented by the following formula Xe:

Formula Xe

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

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

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

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

[000137]

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:

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

Formula VII

And GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I, a' and G 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

Formula Xc in which GpR is a radical of formula VIF.

O

Il R ^H N ^* VIF Formula

And GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I, a' 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 r = l of formula Xc as defined below:

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

VIF formula

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

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

VIF and h = 0.

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

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

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

In one embodiment, r = l, g = 0, GpR is a radical of formula VIF,

GpA is a radical of formula Villa and h = 1.

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

In one embodiment, r = l, g = 0, GpR is a radical of formula VIF, GpA is a radical of formula VUIb and h = 1. In one embodiment, said at least one hydrophobic radical — Hy is chosen from the radicals of formula X as defined below:

Formula X in which GpC is a radical of formula IX in which e = Q and GpC is a radical of formula IXa

Formula IXa

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

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

Formula IXd

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 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

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 following formula Xf:

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, I = 0 and G = 1 represented by the formula Xg next :

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 said hydrophobic radicals are chosen from hydrophobic radicals of formula X in which h = 0, a '= 1 represented by the following formula Xh:

^* - (GpR) - (GpG) - (G p A— GpC

r 'g' to 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:

Formula Xi

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

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent linear alkyl comprising from 2 to 12 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent alkyl comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent linear alkyl comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent alkyl comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent linear alkyl comprising from 2 to 4 carbon atoms. In one embodiment, your composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent alkyl comprising 2 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent linear alkyl comprising from 1 to 11 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent alkyl comprising from 1 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent alkyl, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent linear alkyl, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical chosen from the group consisting of radicals represented by the formulas below:

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula XI.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula X2. In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is linked to co-polyamino acid via an amide function carried by the carbon in delta or epsilon position (or in position 4 or 5) relative to the amide function

(-COIMH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical linear ether or unsubstituted polyether comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical ether.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical ether comprising from 4 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical divalent alkyl comprising 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical ether represented by the formula

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical polyether.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical linear polyether comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical polyether selected from the group consisting of radicals

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula X3.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula X4.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical polyether chosen from the group consisting of the radicals represented by the formulas X5 and X6 below:

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical polyether of formula X5.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical polyether of formula X6.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpG and / or GpH is of formula CG in which G is an alkyl radical comprising 6 carbon atoms represented by the formula Z below:

Formula Z

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xe, Xf, Xg, Xh and Xi is a radical in which the GpG and / or GpH radical is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by the formula Z below:

Formula Z

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xe, Xf, Xg, Xh and Xi is a radical in which the GpG and / or GpH radical is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by - (CH ₂ ) 2-CH (COOH) -,

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xe, Xf, Xg, Xh and Xi is a radical in which the GpG and / or GpH radical is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by -CH ((CH2) 2COOH) -.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xe, Xf, Xg, Xh and Xi is a radical in which the GpG and / or GpH radical is of formula XI in which G is an alkyl radical comprising 3 carbon atoms represented by -CH ₂ -CH- (COOH).

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xe, Xf, Xg, Xh and Xi is a radical in which the GpG and / or GpH radical is of formula XI in which G is an alkyl radical comprising 3 carbon atoms represented by -CH (CH2) COOH) -.

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpA is of formula VIII and in which Ai, A2 or A3 is chosen from the group consisting of the radicals represented by the formulas below:

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the GpC radical of formula IX is chosen from the group consisting of the radicals of formulas IXe, IXf or IXg below represented:

In one embodiment, the composition is characterized in that the hydrophobic radical of formulas X, Xa, Xb, Xb ', Xc, Xc', Xd, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXe, IXf or IXg in which b is equal to 0, corresponding respectively to the formulas IXh, IXi, and IXj below represented:

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpC corresponds to the formula IX or IXe in which b = 0, and corresponds to the formula IXh.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of linear alkyl radicals.

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

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 19 and 14 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of the radicals represented

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of radicals represented by the formulas below:

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 25 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of alkyl radicals represented by the form below:

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of alkyl radicals represented by the formulas below:

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi in wherein 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 is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xb ', Xc, Xc', Xd, Xe, Xf, Xg, Xh and Xi in wherein 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 form ul es below:

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 ³ 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, the hydrophobic radical Hy is chosen from the group of hydrophobic radicals of formula X, in which h is greater than or equal to 2 and GpC is of formula Ixe. In one embodiment, the hydrophobic radical Hy is chosen from the group of hydrophobic radicals of formula X, in which g is greater than or equal to 2 and a, I and h are equal to 0 and GpC is of formula Ixe .

In one embodiment, the composition is characterized in that the hydrophobic radical is chosen from hydrophobic radicals of formula X, Xc ', Xa, Xb, Xb', Xc, Xe, Xg and Xh in which a ' = l and l '= l and in which Cx is chosen from the group consisting of linear alkyl radicals.

In one embodiment, the composition is characterized in that the hydrophobic radical is chosen from hydrophobic radicals of formula X, Xc ', Xa, Xb, Xb', Xc, Xf, Xg and Xi in which a ' = 2 or S '= 2 and in which Cx is chosen from the group consisting of linear alkyl radicals.

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 the hydrophobic radical corresponds to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.15.

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

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

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

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

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

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

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

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X and 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 hydrophobic radical corresponds to formula X and 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 hydrophobic radical corresponds to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0.2.

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

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

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

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

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

41

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

Next 5:

formula XXXa 'in which,

- D independently represents either a -CH2- group (aspartic unit0) or a -CH2-CH2- group (glutamic unit),

- Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas X, in which r = 1 and GpR is a radical of Formula VII,

- Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas X in which r = 0 or r = 1 and GpR is a radical of Formula VIF, or a radical chosen from the group consisting of an H, a linear acyl group in C2 in CIO, a branched acyl group in C4 in CIO, a benzyl, a terminal "amino acid" unit and a pyroglutamate,

- R2 is a hydrophobic radical chosen from the hydrophobic radicals of formulas X in which r = 1 and GpR is a radical of Formula VII, 0 or a radical -NR'R ", R 'and R" identical or different being chosen from the group consisting of H, linear or branched or cyclic C2 to 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 O, N and S;

5 - X represents a cationic entity chosen from the group comprising alkaline cations; - n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of co-polyamino acid and 5 <n + m <250.

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

In one embodiment, the composition according to the invention is characterized in that when the co-polyamino acid comprises aspartate units, then the co-polyamino acid can also comprise monomeric units of formula XXXI and / or CCCG:

Form XXXI Form CCCG

The term “co-polyamino acid with statistical grafting” means a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula XXXa.

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 ', in which Ri = R' i and R2 = R'2, with the following formula XXXa:

Form XXXa

in which,

- m, n, X, D and Hy have the definitions given above, R'i is a radical chosen from the group consisting of an H, a linear acyl group at C2 to CIO, a branched acyl group at C4 to CIO, a benzyl, a terminal "amino acid" unit and a pyroglutamate,

- R is a radical -IMR'R ", R 'and R" identical or different being chosen from the group consisting of H, linear or branched or cyclic C2 to CIO alkyl, benzyl and said R' and R "alkyls which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, N and S.

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, in which Hy is a radical of formula X.

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

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

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula XXXa, in which Hy is a radical of formula X and in which GpC is a radical of formula IX and r = l. In one embodiment, the copolyamino acid is chosen from the copolyamino acids of formula XXXb in which the hydrophobic radical -Hy is chosen from the group of hydrophobic radicals of formula X, Xc ', Xa, Xb', Xc, Xe, Xg and Xh in which a '= 1 and G = 1 and GpC is a radical of formula IXe.

In one embodiment, the copolyamino acid is chosen from the copolyamino acids of formula XXXb in which the hydrophobic radical -Hy is chosen from the group of hydrophobic radicals of formula X, Xc ', Xa, Xb', Xc, Xe, Xg and Xh in which a '= 1 and = 1 and GpC is a radical of formula IX in which e = 0.

In one embodiment, the copolyamino acid is chosen from the copolyamino acids of formula XXXb in which the hydrophobic radical -Hy is chosen from the group of hydrophobic radicals of formula X, Xc ', Xa, Xb, Xc, Xf, Xg and Xi in which a '= 2 or l' = 2 and GpC is a radical of formula IXe.

In one embodiment, the copolyamino acid is chosen from the copolyamino acids of formula XXXb in which the hydrophobic radical -Hy is chosen from the group of hydrophobic radicals of formula X, Xc ', Xa, Xb, Xc, Xf, Xg and Xi in which a '= 2 and l' = 2 and GpC is a radical of formula IX in which e = 0.

In one embodiment, the copolyamino acid is chosen from the copolyamino acids of formula XXXa in which the hydrophobic radical -Hy is chosen from the group of hydrophobic radicals of formula X, Xc ', Xa, Xb', Xc, Xe, Xg and Xh in which a '= 1 and = 1 and GpC is a radical of formula IXe.

In one embodiment, the copolyamino acid is chosen from the copolyamino acids of formula XXXa in which the hydrophobic radical -Hy is chosen from the group of hydrophobic radicals of formula X, Xc ', Xa, Xb, Xc, Xf, Xg and Xi in which a '= 2 or l' = 2 and GpC is a radical of formula IXe.

A “co-polyamino acid with defined grafting” is a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, a copolyamino acid of formula XXXb.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula XXXa 'in which n = 0 of formula Next XXXb:

Form XXXb

in which m, X, D, Ri and R2 have the definitions given above and at least Ri or R2 is a hydrophobic radical of formula X. [000250] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula XXXa 'in which n = 0 of formula XXXb and Ri or R2 is a hydrophobic radical of formula X.

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 XXXb, in which RI = R'1 , of formula XXXb ':

Formula XXXb 'in which m, X, D, R'i and R2 have the definitions given above and R2 is a hydrophobic radical of formula X.

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 co-polyamino acids of formulas XXXb, in which R2 - R'2, of formula XXXb ":

Formula XXXb "in which m, X, D, Ri and R have the definitions given above and Ri is a hydrophobic radical of formula X.

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

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula XXXb or XXXb "in which Ri is a hydrophobic radical of formula X and GpR is of formula VII 'and GpC is of formula IX.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula XXXb or XXXb "in which Ri is a hydrophobic radical of formula X and GpR is of formula VU 'and GpC is of formula IX.

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 XXXb or XXXb 'in which R2 is a hydrophobic radical of formula X in which r = 1 and GpR is of Formula VII.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula XXXa ', in which at least one of the Ri or R2 is a hydrophobic radical as defined above, of formula XXX below:

formula XXX

in which,

- D independently represents either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),

- Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas X in which r = 0 or r = l and GpR is a radical of Formula VII ', or a radical chosen from the group consisting of H, a linear acyl group in C2 to CIO, a branched acyl group from C4 to CIO, a benzyl, a terminal "amino acid" unit and a pyroglutamate,

- R2 is a hydrophobic radical chosen from the hydrophobic radicals of formulas X in which r = 1 and GpR is a radical of Formula VII, or a radical -NR'R ", R 'and R" identical or different being chosen from the group consisting of H, linear or branched or cyclic C2 to 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 in the group made up of O, N and S, - at least one of Ri or R2 is a hydrophobic radical as defined above,

- X represents an H or a cationic entity chosen from the group comprising metal cations;

- n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of 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 hydrophobic radicals is chosen from the co-polyamino acids of formula XXX, XXXa, XXXa ′, XXXb, XXXb 'or XXXb "in which group D is a group -CH ₂ - (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 formula XXX, XXXa, XXXa ', XXXb, XXXb 'or XXXb ”in which group D is a group -CH2-CH2- (glutamic unit).

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 C ₄ 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 C ₄ 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, XXXb, XXXb 'or XXXb " in which the co-polyamino acid is chosen from co-polyamino 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 XXXb, XXXb 'or XXXb "in which the co-polyamino acid is chosen from the co-polyamino acids in which the group D is a group -CH2-CH ₂ - (glutamic unit). 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 XXXXa below

Formula XXXXa in which,

D independently represents either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),

X represents a cationic entity chosen from the group comprising alkaline cations,

Ra and R'a, identical or different, are either a hydrophobic radical -Hy, or 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,

- at least one of Ra and R'a being a hydrophobic radical -Hy,

Q has the meaning given above

-Hy has the meaning 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.

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 XXXXa in which R _a and R ' _a , which are identical, are a hydrophobic radical -Hy.

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 XXXXa in which R _a and R ' _a , different are hydrophobic radicals -Hy. 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 XXXXa in which R _a is a hydrophobic radical -Hy and R ' _a is not a hydrophobic radical -Hy.

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 XXXXa in which R ' _a is a hydrophobic radical -Hy, and R _a is not a hydrophobic radical -Hy.

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 XXXXa 'below :

Formula XXXXa '

In which :

D, X, Ra and R'a have the definitions given above,

Q and Hy have the meanings given above,

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,

ni + n2 = n 'and mi + r = m' 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.

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 XXXXa 'in which Ra and R'a, identical are a hydrophobic radical -Hy.

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 XXXXa 'in which Ra and R'a, different are hydrophobic radicals -Hy.

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 XXXXa 'in which Ra is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.

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 XXXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.

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 XXXXb below:

Formula XXXXb in which,

D and X have the definitions given above, Rb and R'b, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid" unit and a pyroglutamate,

at least one of Rb and R'b is a hydrophobic radical -Hy,

Q and Hy have the meanings given above.

n + m has the same definition as given above.

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 XXXXb in which Rb and R'b, identical, are a hydrophobic radical -Hy.

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 XXXXb in which Rb and R'b, different are hydrophobic radicals -Hy.

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 XXXXb in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.

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 XXXXb in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.

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 XXXXb 'below :

Formula XXXXb '

in which :

D and X have the definitions given above,

Q and Hy have the meanings given above.

Rb and R'b, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of -OH, an amine group, a unit

Terminal "amino acid" and a pyroglutamate,

at least one of Rb and R'b is a hydrophobic radical -Hy,

n l + ml represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid carrying a radical -Hy,

n2 + m2 represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid not carrying a -Hy radical,

n l + n2 = n 'and m l + m2 = m',

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.

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 XXXXb 'in which Rb and R'b, identical, are a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at WO 2019/243628 PCT / EP2019 / 066614

54

at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXXb 'in which Rb and R'b, different are hydrophobic radicals -Hy.

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 XXXXb ' in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.

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 XXXXb 'in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.

In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXXa, XXXXb, XXXXa 'or XXXXb' in which the group D is a group -CH2-CH2- (glutamic unit).

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXXa, XXXXa ', XXXXb' in which group D is a group -CH2- (aspartic unit).

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

5

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 XXXX and / or XXXX ' :

0

Formula XXXX Formula XXXX ' WO 2019/243628 PCT / EP2019 / 066614

55

“Co-polyamino acid with statistical grafting” is a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, represented by a co-polyamino acid of formula XXXXa 'and XXXXb'.

Called "co-polyamino acid with defined grafting" a co-polyamino acid 5 carrying carboxylate charges and at least one hydrophobic radical, represented by a co-polyamino acid of formula XXXXa and XXXXb.

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-polyaminoacid0 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. [000296] In one embodiment, the concentration of co-polyamino acid carrying Carboxylate and hydrophobic radical charges 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. When the copolyamino acid is chosen from the copolyamino acids of formulas XXXXa, XXXXb, XXXXa 'or XXXXb' it can be represented by a copolyamino acid of formula XXXI:

[Q (PLG) k] [HyMHy '

5 Formula XXXXI

In which :

- j> 1; 0 <j '<n'I and j + j' ³ 1 and k> 2

- Said co-polyamino acid of formula XXXXI being carrying at least one hydrophobic radical -Hy, of carboxylate charges and consisting of at least two chains of glutamic or aspartic PLG units linked together by a radical or spacer Q [- * ] k linear or branched at least divalent 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 oxygen and / or radicals carrying one or more heteroatoms consisting of 5 nitrogen and oxygen atoms and / or carboxyl functions,

said radical or spacer Q [- *] i _< being linked to at least two chains of glutamic or aspartic units PLG by an amide function and, - Said amide functions linking said radical or spacer Q [- *] _k linked 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 [- *] k either by a glutamic or aspartic unit,

- Said hydrophobic radical -Hy being linked either to a terminal "amino acid" unit and then j> 1, or to a carboxyl function carried by one of the chains of glutamic or aspartic units P LG and then j '= n'I and n '1 is the average number of monomeric units carrying a hydrophobic radical -Hy.

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 XXXXXa below:

Formula XXXXXa in which,

• D independently represents either a -CHz- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),

• X represents a cationic entity chosen from the group comprising alkaline cations,

• 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,

• 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;

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 XXXXXa in which R _a and R ' _a , which are 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 XXXXXa 'below :

Formula XXXXXa '

In which :

• D independently represents either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit),

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

Ni + iTii 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,

• hi + P2 = n and rm + r = m 58

• p + 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 XXXXXa " next :

0

Formula XXXXXa "

In which :

5 • X represents a cationic entity chosen from the group comprising alkaline cations,

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

• Ra 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 co-polyamino acid and 5 <n + m <250;

5 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 XXXXXb below:

formula XXXXXb in which,

• D independently represents either a -CH ₂ - group (aspartic unit) or a -CH2-CH2- group (glutamic unit),

•

• Rb and R'b, 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 alkyl, the benzyl and said R 'and R "alkyls which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, IM 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. 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 XXXXXb 'below :

Formula XXXXXb '

in which :

• D independently represents either a group -Chh- (aspartic unit) or a group -CH2-CH2- (glutamic unit),

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

• Rb and R 'b, 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 alkyl, the benzyl and said R 'and R "alkyls which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, IM and S;

• n l + 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 not carrying a -Hy radical

• n l + n2 = n and m l + m2 = m

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; 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 XXXXXb "below :

Formula XXXXXb ''

In which :

· X represents a cationic entity chosen from the group comprising alkaline cations,

• Rb and R'b, 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 alkyls to CIO, benzyl and said R 'and R "alkyls which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, N and S;

· 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. [000306] In a mode of embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from co-polyamino acids XXXXXa, XXXXXa ', XXXXXa ", XXXXXb, XXXXXb" and XXXXXb "in which the group D is a group -CH2- (aspartic unit).

[000307] 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 XXXXXa, XXXXXa ', XXXXXa ", XXXXXb, XXXXXb 'and XXXXXb "in which the group D is a group -CH2- CH2- (glutamic unit).

When the co-polyamino acids are copolyamino acids of formulas XXXXXa, XXXXXa ', XXXXXa ", XXXXXb, XXXXXb' or XXXXXb" it may be represented by a co-polyamino acid of formula CCCCCI ':

Q [Hy] _j] [PLG] k [Hy] _h y [Hy] _hy ·

CCCCCI 'formula

In which :

j> 1; k> 2

hy> 0 and hy '> 0

said co-polyamino acid of formula CCCCCI ′ 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> 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 d oxygen and / or radicals carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions, said radical Q [- *] i 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 [- *] i being linked to at least one hydrophobic — Hy radical 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 [- *] i 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 carried either by the precursor Q 'of the radical or spacer Q [- *], or by the precursor Hy 'of the hydrophobic radical — Hy; and - When hy and hy '¹ 0 then at least one hydrophobic radical -Hy is linked either to a terminal “amino acid” unit, or to a carboxyl function carried by one of the chains of PLG glutamic or aspartic units.

[000310]

The radicals or spacers Q [- *] i (i> 3) or Q [- *] k can be represented by a radical of formula QII:

Q [- *] l = ([Q1

IQ formula

In which 1 <q <5

The radicals Q 'being identical or different and chosen from the group consisting of the radicals of formulas QUI to QVI below, to form Q [- *] i (i> 3)

QIV formula

In which :

At least one of the ui "or m” is different from 0.

If ui "¹ 0 then ui '¹ 0 and if U2" ¹ 0 then U2' ¹ 0,

ui 'and U2' are the same or different and,

2 <u <4,

0 <ui '<4,

0 <ui "<4,

0 <U2 '£ 4

0 <U2 "<4 and,

QV formula

In which :

v, v 'and v "identical or different, v + v '+ V "£ 15

QVI formula

In which :

w'i is different from O,

0 £ w " ₂ <1,

wi <6 and w'i <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 functions -N H- 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 = -N H- or Fy = -N =, thus forming an amide bond.

[000313]

In one embodiment, if Fa and Fa 'are -NH-, then t> 2.

In one embodiment, if Fa and Fa 'are -CO-, then t³ l.

In one embodiment, if Fa and Fa 'are -CO- and -N H-, then t³ l.

In one embodiment, if Fb and Fb 'are -NH-, then u and ui'³2 and / or u ₂ ' ³2.

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.

[000321] 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 w'1> 2 and / or w2 and w "2> 2.

In one embodiment, if Fd and Fd 'are -CO-, wl and w'1> 1 and / or w2 and w "2> 1.

In one embodiment, if Fd and Fd 'are -CO- and -NH-, wl and w'1> 1 and / or w2 and w "2> 1. Hy and PLG being linked to Q [- *] i by an Fx or Fy function by a covalent bond to form an amide bond with an -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

Formula WHO

whose precursor is a diamine.

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

In one embodiment, t = 2 and the precursor of the radical of formula QUI is ethylene diamine.

In one embodiment, t = 4 and the precursor of the radical of formula QUI is butylenediamine.

In one embodiment, t = 6 and the precursor of the radical of formula QUI is hexylenediamine.

In one embodiment, t = 3 and the precursor of the radical of formula QUI is 1,3-diaminopropane.

In one embodiment, t = 5 and the precursor of the radical of formula QUI is 1,5-diaminopentane.

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

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

In one embodiment, t = 2 and and the precursor of the radical of formula QUI is beta-alanine.

In one embodiment, t = 6 and and the precursor of the radical of formula QUI is aminohexanoic acid.

In one embodiment, t = 4 and the precursor of the radical of formula QUI is aminobutanoic acid.

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

In one embodiment, t = 2 and and the precursor of the radical of formula QUI is succinic acid.

In one embodiment, t = 3 and the precursor of the radical of formula QUI is glutaric acid.

In one embodiment, t = 4 and the precursor of the radical of formula QUI is adipic acid.

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

QIV formula whose precursor is a diamine.

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

In one embodiment, u = u'i = 2, u "i = l, u" 2 = 0 and the precursor of the radical of formula QIV is diethylene glycol diamine.

In one embodiment, u = u'i = u'2 = 2, u "i = u" 2 = 1 and the precursor of the radical of formula QIV is triethylene glycol diamine.

In one embodiment, u = u'2 = 3, u'i = 4, u "i = u" 2 = 1 and the precursor of the radical of formula QIV is 4,9-dioxa-1, 12-dodecane.

In one embodiment, u = u'2 = 3, u'i = u "i = 2, u" 2 = 1 and the precursor of the radical of formula QIV is 4,7,10-trioxa- l, 13-tridecanediamine.

[000351]

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

Q v,

QV formula [000353] the precursor of which is chosen from the group consisting of amino acids.

In one embodiment, the precursor of the radical of formula QV is an amino acid chosen from the group consisting of lysine, ornithine and 2,3-diaminopropionic acid.

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

QV formula

the precursor of which is chosen from the group consisting of triacids.

In one embodiment, the precursor of the radical of formula QV is a triacid chosen from the group consisting of tricarballylic acid.

In one embodiment, v = 0, v '= v "= 1 and the precursor of the radical of formula QV is tricarballylic acid. In one embodiment, at least one of the Q' is a radical of formula

QV formula

the precursor of which is chosen from the group consisting of triamines.

In one embodiment, the precursor of the radical of formula QV is a triamine chosen from the group consisting of (2- (aminomethyl) propane-1,3-diamine).

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

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

Formula

IRT

whose precursor is a triamine.

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

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

In one embodiment, w "i = 0 and the precursor of the radical of formula QVI is diethylenetriamine.

An embodiment, w "i = 0 and the precursor of the radical of formula QVI is bis (hexamethylene) triamine.

In one embodiment, w "2 = l and the precursor of the radical of formula

QVI is a tetramine.

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

In one embodiment, w "2 = 1 and the precursor of the radical of formula

QVI is spermine.

In one embodiment, w "2 = 1 and the precursor of the radical of formula QVI is triethylenetetramine. In one embodiment, the PLGs are linked to Fx with Fx = -NH- or to Fy by at least a carbonyl function of 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 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 relates to the co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic Hy radicals chosen from the radicals of formula X as defined above below:

Formula X in which

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

;

- GpG and GpH identical or different are chosen from the radicals of formulas XI or XI ':

NH - G - NH- Form XI Form CG

GpA is chosen from the radicals of formula VIII

Formula VIII

In which A 'is chosen from the radicals of formula HIV', VIII "or VIII '

Form VIII 'Form VIII' Form VIII '

-GpL is chosen from the radicals of formula XII

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; 71

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;

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

e is an integer equal to O 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, and at least one of the g, h or

I is different from 0;

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

r is an integer equal to 0, 1 or 2, 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 8 carbon atoms, and optionally substituted5 by a radical derived from a saturated, unsaturated or aromatic ring;

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

0 Cx is a linear or branched monovalent alkyl radical optionally comprising a cyclic part, 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 <13.5 * 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 linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s), 0 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 -CONH ₂ 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 the PLG:

o via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by the PLG thus forming an amide function derived of the reaction of an amine function carried by P LG 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 the PLG 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 PLG, the ratio M between the number of hydrophobic radicals and the number d 'glutamic or aspartic units being between 0 <M <0.5;

The invention also relates to the precursor Hy ′ of the hydrophobic radical - Hy of formula X ′ as defined below:

Formula X '

in which

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

;

- GpG and GpH identical or different are chosen from the radicals of formulas XI or CG:

* - NH - G - NH -

Form XI Form CG

GpA is chosen from the radicals of formula VIII

Formula VIII

In which A 'is chosen from the radicals of formula HIV', HIV "or VIII" '

Form VIII 'Form VIII "Form VIII'"

-GpL is chosen from the radicals of formula XII

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;

- 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;

I is different from 0;

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

r is an integer equal to 0, 1 or 2, 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 8 carbon atoms, and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring;

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

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

* 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 linear or branched alkyl radical divalent from 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 PLG:

via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by the PLG thus forming an amide function resulting from the reaction of an amine function carried by the PLG 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 the PLG 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 PLG,

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

the free carboxylic acid functions being in the form of an alkali cation salt chosen from the group consisting of Na ⁺ and K ⁺ . The co-polyamino acids may in particular be those described in applications WO2017 / 211916, W02017 / 2U903, W02019 / 110625, WO2019 / 038445 and WO2019 / 110773. [000390] The hydrophobic radical ratio by basal insulin is defined as being the ratio of their respective molar concentrations: [Hy] / [basal insulin] (mol / mol) to obtain the expected performance, namely the solubilization of basal insulin at pH between 6.0 and 8.0, the precipitation of basal insulin and the 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.

[000393] 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.

[000395] In one embodiment, the hydrophobic radical ratio by basal insulin

[Hy] / [basal awareness! <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.

[000398] In one embodiment, the hydrophobic radical ratio by basal insulin

[Hy] / [basal insulin] £ 0.75.

[000399] 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. [000401] In one embodiment, the compositions according to the invention comprise a mealtime insulin. Prandial insulins are soluble at pH 7.

[000402] By mealtime insulin is meant a so-called rapid or "regular" insulin. The 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 main insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.

[000406] Human insulin is marketed under such brands Humulin ^® (Eli Lilly) and Novolin ^® (Novo Nordisk).

[000407] 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.

[000408] In one embodiment, the prandial insulins say very fast (fast acting) are selected from the group consisting of insulin lispro (Humalog ^®), insulin glulisine (Apidra ^®) and insulin aspart (NovoLog ^® ).

[000409] In one embodiment, the meal insulin is lispro insulin.

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 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 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 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 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 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.

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 achieved.

[000424] In one embodiment, the compositions according to the invention comprise a gastrointestinal hormone.

By “gastrointestinal hormones” is meant 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 proglucagon), peptide YY, S'amyline, 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.

[000427] In one embodiment, the gastrointestinal hormone is pramlintide or Symlin ^{® ®} (ASTRA-ZENECA). In one embodiment, the gastrointestinal hormone is exenatide or Byetta ^® , its analogs or derivatives and their pharmaceutically acceptable salts.

[000429] In one embodiment, the hormone is gastrointestinal liraglutide or Victoza ^®, 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.

[000431] In one embodiment, gastrointestinal hormone is albiglutide or Tanzeum ^®, 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 by other residues d amino acids and / or in which one or more constituent amino acid residues have been deleted and / or in which one or more constitutive amino acid residues have been added. The percentage of homology accepted for the present definition of an analogue is 50%.

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

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

In one embodiment, the concentration of gastrointestinal hormone is in the range of 0.01 to 100 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.

[000445] 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 exenatide.

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 liraglutide.

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, the isoelectric point of which 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, the isoelectric point of which 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, from 0.04 to 0.5 mg / mL of 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.

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

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 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.

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

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

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

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

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

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.

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

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, from 0.01 to 1 mg / ml of lixisenatide.

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

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.

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, from 0.01 to 1 mg / ml of lixisenatide.

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

5.8 and 8.5 and 0.1 to 10 mg / mL of 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, from 0.1 to 10 mg / ml of 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, from 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 composition according to the invention is characterized in that the NI ratio 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 NI ratio 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 the hydrophobic radical corresponds to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is included between 0.01 and 0.1.

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

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

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.06. In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 200.

[000501] In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 65.

The invention further relates to a method for preparing stable injectable compositions. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid comes from a polyamino acid obtained by polymerization.

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

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

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

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of an N-carboxyanhydride derivative 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 co-polyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using as initiator hexamethyldisilazane as described in the publication J. Am. Chem. Soc. 2007, 129,

14114-14115 (Lu H .; et al.) Or a silylated amine as described in the publication J. Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H.; et al.).

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

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

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

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

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

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

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

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

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

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

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

The term “basal insulin”, the isoelectric point of which is between 5.8 and 8.5, is understood to mean insulin which is insoluble at pH 7 and whose duration of action is between 8 and 24 hours or greater in standard models of diabetes. .

These basal insulins, the isoelectric point of which 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, the isoelectric point of which 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.

Insulin glargine biosimilar is approved under the brand Abasaglar ^® or Basaglar ^® by ELI LILLY.

[000536] A biosimilar Insulin glargine is approved under Semglee ^® brand by Mylan and biocon. [000537] A biosimilar Insulin glargine is approved under my RQUE Lusduna ^® by Merck.

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 66 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 75 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 250 U / ml of basal insulin, the isoelectric point of which is between

5.8 and 8.5.

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 co-polyamino acid / basal insulin, is between 0.2 and 8.

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.

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 40 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 comprise a mealtime insulin. Prandial insulins are soluble at pH 7.

By mealtime insulin is meant a rapid or "regular" insulin.

The 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. [000568] Human insulin is marketed under such brands Humulin ^® (Eli Lilly) and Novolin ^® (Novo Nordisk).

[000569] 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.

[000570] In one embodiment, the prandial insulins say very fast (fast acting) are selected from the group consisting of 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 insulin aspart.

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 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 prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5. WO 2019/243628 PCT / EP2019 / 066614

91

In one embodiment, the compositions according to the invention comprise a total of 266 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

5 include a total of 200 U / mL of insulin with a combination of mealtime insulin and basal insulin with an isoelectric point 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 mealtime insulin and basal insulin, the isoelectric point of which is between 5.8 and 8, 5.

0

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

The term “gastrointestinal hormones” means the hormones selected from the group consisting of GLP-1 RA (Glucagon like peptide-1 receptor agonist) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative 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 ^® (ASTRAZEN ECA), 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.

[000589] In one embodiment, the gastrointestinal hormone is pramlintide or Symlin ^{® ®} (ASTRA-ZENECA).

In one embodiment, the gastrointestinal hormone is exenatide or Byetta ^® , its analogs or derivatives and their pharmaceutically acceptable salts. [000591] 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. [000593] In one embodiment, gastrointestinal hormone is albiglutide or Tanzeum ^®, analogs or derivatives and their pharmaceutically acceptable salts.

[000594] In one embodiment, gastrointestinal hormone is Dulaglutide or Trulicity ^®, analogs or derivatives and their pharmaceutically acceptable salts.

[000595] In one embodiment, the hormone is pramlintide or gastrointestinal Symlin ^®, analogs or derivatives and their pharmaceutically acceptable salts.

The term "analog" means, 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%.

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.

[000607] 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 500 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 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, from 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.

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

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

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, from 0.01 to 1 mg / mL of lixisenatide.

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

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

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

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, from 0.01 to 1 mg / mL of lixisenatide.

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

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

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

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

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 .

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

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

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

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, from 0.1 to 10 mg / ml of 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 75 U / ml (or approximately 3.6 mg / ml) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and of 0.04 to 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise 75 U / ml (or approximately 3.6 mg / ml) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and of 1 to 10 mg / mL of liraglutide.

In one embodiment, the compositions according to the invention comprise 75 U / ml (or approximately 3.6 mg / ml) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and of 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 75 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 75 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and 0.1 to 10 mg / ml of 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 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 further comprise zinc salts at a concentration between 0 and 5000 mM.

In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration between 0 and 4000 mM.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 3000 pM.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 2000 pM.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 1000 pM.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 50 and 600 pM.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 100 and 500 pM.

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

In one embodiment, the compositions according to the invention also 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 the Tris

(Trishydroxymethylaminomethane).

[000667] 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 tonicity 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.

[000679] 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 and a mealtime 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 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. WO 2019/243628 PCT / EP2019 / 066614

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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 5 and 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 que0 defined previously.

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 5 and 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 prandial insulin and a gastrointestinal hormone, such as 0 previously defined.

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

In one embodiment, the basal insulin whose isoelectric point5 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.

0

[000693] In one embodiment, the prandial insulin is selected from the group consisting of insulin lispro (Humalog ^®), insulin glulisine (Apidra ^®) and insulin aspart (NovoLog ^®).

In one embodiment, the mealtime insulin is insulin lispro.5 [000695] In one embodiment, the mealtime 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.

[000698] In one embodiment, the gastrointestinal hormone is exenatide.

[000699] In one embodiment, the gastrointestinal hormone is liraglutide.

[000700] In one embodiment, the gastrointestinal hormone is lixisenatide.

[000701] In one embodiment, the gastrointestinal hormone is albiglutide.

[000702] In one embodiment, the gastrointestinal hormone is 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.

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, 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 of which the isoelectric point is between 5.8 and 8.5, of a mealtime insulin solution, a solution of GLP-1 RA or an analog or derivative of GLP-1 RA and 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.

In one embodiment, the mixture of basal insulin and co-polyamino acid is concentrated by ultrafiltration before mixing with the prandial 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 ;

FIG. 1 represents the pharmacokinetic profiles of basal insulin concentrations (sum of glargine and its metabolites glargine-Ml and glargine-M2) after subcutaneous administration of the composition CB3 'at 0.8 U / kg (solid circles) in T2D patients (n = 31) - arithmetic means ± SE. On the abscissa is represented time (in hours), on the ordinate is represented the concentration (in pmol / L).

FIG. 2 represents the median curve of the insulin glargine concentration (also including the insulin Ml concentration) after administration of the composition CB3b in dogs at a dose of 0.67 U / kg. In this Figure, the median insulin glargine concentration values, in pmol / L, are represented on the ordinate, and the post-injection time, in hours (h), is represented on the abscissa.

Examples

The invention is described in more detail through the following examples in a non-limiting manner.

RECTIFIED SHEET (RULE 91) ISA / EP [000714] Part A - Examples of copolyamino acids

The copolyaminacids below exemplified are described in applications WO2017 / 211916, W02017 / 211903, W02019 / 110625 and WO2019 / 038445.

r7

Table la: List of co-polyamino acids synthesized according to the invention

Synthesis of BB15 co-polyamino acid Example BA3: BA3 molecule

Molecule B7: product obtained by the reaction between myristic acid and L-proline.

To a solution of myristic acid (18.93 g, 82.91 mmol) in THF (520 mL) at 0 ° C are successively added dicyclohexyl carbodiimide (DCC) (16.29 g, 78.96 mmol) and N-hydroxysuccinimide (NHS) (9.09 g, 78.96 mmol). After 60 h of stirring at room temperature, the medium is cooled to 0 ° C for 20 min, filtered through a frit. L-proline (10 g, 86.86 mmol), diisopropylethylamine (DIPEA) (68.8 mL) and water (60 mL) are added to the filtrate. After 24 h of stirring at room temperature, the medium is diluted with water (300 mL). The aqueous phase is washed with WO 2019/243628 PCT / EP2019 / 066614

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ethyl acetate (2 x 250 mL), acidified to pH ~ 1 with an aqueous solution of HCl IN and then extracted with dichloromethane (3 x 150 mL). The combined organic phases were dried over Na2S0 _4, filtered, concentrated in vacuo and the residue was purified by chromatography on silica gel (cyclohexane, ethyl acetate) to give 5 a yellowish oil.

Yield: 20 g (78%).

1 H NMR (CDCb, ppm): 0.88 (3H); 1.28 (20H); 1.70 (2H); 1.90-2.10 (3H); 2.36 (2H); 2.51 (1H); 3.47 (1H); 3.56 (1H); 4.61 (1H).

LC / MS (ESI): 326.2; (calculated ([M + H] ⁺ ): 326.6).

10 Molecule B8: product obtained by the reaction between the molecule B7 and L-lysine

By a process similar to that used for the preparation of the B7 molecule applied to the B7 molecule (20.02 g, 61.5 mmol) and to L-lysine (4.72 g, 32.29 mmol) , a white solid is obtained.

Yield: 12.3 g (53%).

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

LC / MS (ESI): 761.8; (calculated ([M + H] ⁺ ): 762.1).

20 Molecule B9: product obtained by the reaction between Boc-ethylenediamine and the molecule

B8.

To a solution of molecule B8 (12 g, 15.77 mmol) in THF (170 mL) are added DIPEA (8.80 mL) and 2- (1H-benzotriazol-1-yl) - 1,1,3,3- tetramethyluronium tetrafluoroborate (TBTU, 8.52 g, 26.54 mmol) at room temperature. After 30 min of stirring, Boc-ethylenediamine (3.03 g, 18.92 mmol) is added. After stirring at room temperature for 2 h, the solvent is evaporated off under reduced pressure and the residue is diluted with ethyl acetate (400 ml). The organic phase is washed with water (250 ml), a saturated aqueous solution of NaHCCh (250 ml), an aqueous solution of 1 N HCl (250 ml), an aqueous solution saturated with 30 NaCl (250 ml) and was dried over Na2S0 _4. After filtration and concentration under vacuum, the residue obtained is purified by chromatography on silica gel (ethyl acetate, methanol) to give a colorless oil.

Yield: 12.5 g (88%).

NMR (DMSO-de, ppm): 0.85 (6H); 1.20-1.55 (55H); 1.50-2.25 (14H); 2.95-3, 10 35 (6H); 3.31-3.55 (4H); 4.10-4.40 (3H); 6.74 (1H); 7.60-8.25 (3H).

LC / MS (ESI): 904.1; (calculated ([M + H] ⁺ ): 904.3). BA3 molecule

To a solution of the molecule B9 (12.5 g, 13.84 mmol) in dichloromethane (110 mL) at 5 ° C is added a solution of 4N HCl in dioxane (20.2 mL). After 20 h of stirring at 5 ° C, the medium is concentrated in vacuo. The residue obtained is dissolved in methanol and evaporated in vacuo, this operation being repeated 4 times to give a white solid of molecule BA3 in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 9.2 g (79%).

1 H NMR (DMSO-de, ppm): 0.85 (6H); 1.10-1.65 (48H); 1.70-2.35 (12H); 2.85 (2H); 3.01 (2H); 3.25-3.65 (6H); 4.10-4.50 (3H); 7.70-8.40 (6H).

LC / MS (ESI): 803.9; (calculated ([M + H] ⁺ ): 804.2).

Example BB15: co-polyamino acid BB15 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 3610 g / mol

In a suitable container are successively introduced the hydrochloride salt of the molecule BA3 (3.62 g, 4.32 mmol), chloroform (40 mL), 4 A molecular sieve (1.5 g), as well than Amberlite IRN 150 ion exchange resin (1.5 g). After 1 h of stirring on rollers, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then co-evaporated with toluene. The residue is dissolved in anhydrous DMF (20 mL) to be used directly in the polymerization reaction.

In a flask previously dried in an oven, g-benzyl-L-glutamate N-carboxyanhydride (25.0 g, 94.97 mmol) is placed under vacuum for 30 min and then

Anhydrous DMF (100 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of BA3 molecule prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to ambient temperature then poured dropwise into diisopropyl ether (1.2 L) with stirring. The white precipitate is recovered by filtration, washed twice with diisopropyl ether (100 ml) and then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (105 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (38 mL, 220 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (600 mL). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed WO 2019/243628 PCT / EP2019 / 066614

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successively with a 1: 1 (v / v) mixture of diisopropyl ether and water (200 mL) then with water (100 mL). The solid obtained is dissolved in water (450 mL) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. The mixture is filtered on a 0.45 μm filter and is then purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to approximately 30 g / L theoretical and the pH is adjusted to 7.0. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 26.5 mg / g.

10 PD (estimated by NMR ^! H) = 24 therefore i = 0.042.

The calculated average molar mass of the co-polyamino acid BB15 is 4390 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3610 g / mol.

[000724]

15 Synthesis of Co-polyamino acid BX2

Table 1: Structure of the hydrophobic molecule precursor of the hydrophobic radical before grafting on the co-polyamino acid BX2.

20 Example AX3: AX3 molecule

The AX3 molecule is obtained by the conventional method of solid phase peptide synthesis (SPPS) on 2-chlorotrityle chloride (CTC) resin (40.00 g, 1.16 mmol / g). The grafting of ethylene diamine (20.0 equivalents) is carried out in DCM (10 V). The unreacted sites are capped with methanol (0.8 ml / g resin) at the end of the reaction.

The couplings of the protected amino acids Fmoc-Lys (Fmoc) -OH (1.5 equivalents), Fmoc-Glu (OtBu) -OH (2.5 equivalents) and of molecule 1 (2.5 equivalents) are performed in DMF (10 V), in the presence of HATU (1.0 equivalent with respect to the acid) and DIPEA (1.5 equivalents with respect to the acid).

The protective groups Fmoc are removed using a solution of DMF / piperidine 80:20 (10 V).

The product is cleaved from the resin using a DCM / TFA 50:50 solution

(10 V). After evaporation, the residue is dissolved in water (600 mL), the pH of the solution is adjusted to 7 by adding a 5N NaOH solution, then the product is lyophilized. The lyophilisate is purified by column chromatography on silica gel (dichloromethane, methanol, NhUOH) to give the molecule AX3 in the form of a white solid.

Yield: 24.6 g (50% overall over 7 steps).

eOD-d4, ppm): 0.90 (6H); 1.18-2.45 (68H); 2.45-2.60 (2H); 3.05-3.11 -3.19 (1H); 3.23-3.33 (1H); 3.43-3.66 (4H); 3.82-3.94 (2H); 4.10 to 4.51

I +): 1061.9 (calculated ([M + H] ⁺ ): 1061.8).

Example BX2: Co-polyamino acid BX2 - Sodium poly-L-glutamate modified at one of its ends by the molecule AX3 and having a number-average molar mass (Mn) of 2100 g / mol

In a flask previously dried in an oven, y-benzyl-L-glutamate

N-carboxyanhydride (72.46 g, 275.2 mmol) is dissolved in anhydrous DMF (270 mL). The mixture is then stirred until complete dissolution, cooled to 0 ° C, then a solution of the AX3 molecule (13.28 g, 12.51 mmol) in CHCl3 (53 mL) is introduced quickly. The mixture is stirred between 0 ° C and room temperature for 18 h, then heated to 65 ° C for 2 h. About half of the solvent is removed by distillation then the reaction mixture, cooled to room temperature, is poured dropwise into diisopropyl ether (2.4 L) with stirring. The white precipitate is recovered by filtration, washed twice with diisopropyl ether and then dried under reduced pressure at 30 ° C to obtain a white solid.

It is solubilized in DMAc (300 mL) then Pd / AhCh (6.0 g) is added under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (10 bar) and stirred at 60 ° C for 24 h. After cooling to room temperature and filtration of the catalyst on a sintered P4 then on an Omnipore 0.2 pm PTFE membrane hydrophilic, a solution of water at pH 2 (6 V) is poured dropwise onto the DMAc solution, over a period of 45 min and with stirring. After 18 h with stirring, the white precipitate is recovered by filtration, washed with water and then dried under reduced pressure. The solid obtained is dissolved in water (2.2 L) by adjusting the pH to 7 by adding a 1N aqueous sodium hydroxide solution. The pH is then adjusted to pH 12 and the solution is stirred for 1 hr. After neutralization at pH 7, the solution is filtered over 0.2 μm, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, then filtered on an activated carbon filter (3M R53SLP).

The solution obtained is filtered through 0.45 μm and purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered over 0.2 μm and stored at 4 ° C.

Dry extract: 29.9 mg / g

DP (estimated by ¹ H NMR) = 23

According to the NMR * H: i = 0.043

The calculated average molar mass of the co-polyamino acid BX2 is 4541 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2100 g / mol.

PART C - COMPOSITIONS

Part Cl - Basal Insulin Compositions

Insulin solution. slow analog. (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), polysorbate 20 (16 mM) sodium hydroxide and hydrochloric acid for adjusting the pH (pH 4) and water.

diluted composition co-polyamino acid / insulin glargine 50 U / mL to

î el j i gu id e (in soil uti on).

To a stock solution of co-polyamino acid at pH 7, 1 are added concentrated solutions of m-cresol and glycerin so as to obtain a solution of co-polyamino acid of concentration Cmère co-po _lya minoacid _{/ e} xcipients ( mg / mL). The amount of added excipients is adjusted so as to obtain a concentration of m-cresol of 35 mM and glycerin of 184 mM in the co-polyamino acid / insulin glargine composition 50 U / ml at pH 7.1.

[000733] In a sterile container, a volume of a Vmsuime glargine insulin glargine commercial solution marketed under the name Lantus ^® at a concentration of 100 U / ml is added to a volume co-Vmère poiyaminoacide / excipients a solution of co-polyamino acid at the concentration C co-polyamino acid / excipients (mg / ml) so as to obtain a dilute composition co-polyamino acid C diluted co-polyamino acid (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 hours until complete dissolution. This visually clear solution is placed at + 4 ° C.

[000734] The composition of co-polyamino acid / insulin glargine 50 U / mL at pH 7.1 described above is concentrated by ultrafiltration over a 3 kDa membrane regenerated cellulose (Amicon Ultra-15 ^® commercialized by Millipore Corporation). 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 Cmsuime glargine (U / mL) and a concentration of co-polyamino acid Cco-polyamino acid (mg / mL) = Cco-po! Diluted yamino acid (my / m L) X Cinsulin glargine (U / mL) / 50 (U / mL).

According to this process, the co-polyamino acid / insulin glargine compositions described in the table below were prepared with insulin glargine concentrations of 200 U / ml.

Table 3: Co-polyamino acid / insulin glargine compositions (200 U / mL) prepared with co-polyamino acids Part C2 - Compositions of rapid analogue insulin and basal insulin

Rapid analog insulin solution (Humalog ^® ! At 100 U / mL

This solution is a commercial insulin lispro solution marketed 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. Analog insulin solution rim (Lantys i at 100 U / mL

[000737] This solution is an insulin glargine commercial solution marketed by 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), polysorbate 20 (16 mM) sodium hydroxide and hydrochloric acid for adjusting the pH (pH 4) and water. Preparation of a dilute composition co-polvamino acid / insulin olaraine 43 (U / mL) / insulin _,

To a volume Vco-polyaminoaclde / insulin glargine diluted from the diluted composition co-polyaminoacid / insulin glargine 50 U / ml at pH 7.1 described in part C1 is added a volume Vinsuiine iispro 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) composition.

[000739] The composition of co-polyamino acid / insulin glargine 43 (U / mL) / insulin lispro 13.5 (U / ml) described above is concentrated by ultrafiltration over a 3 kDa membrane of regenerated cellulose (Amicon ^® Ultra-15 marketed 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 concentrated HCl. This visually clear pH 7,1 solution has a concentration of insulin glargine

Cinsulin glargine (U / mL), a concentration in î n SU I ί ne lispro Cinsuüne lispro ⁼ Cinsulin glargine X 0.33 and a concentration of co-polyamino acid Cco-poiyaminoadde (mg / mL) = Cco-poiyaminoadde diluted (mg / mL) X Cinsulin glargine (U / mL) / 50 (U / mL).

Co-polvamino acid BB15 / insulin _qlargin 200 U / mL / insulin lispro composition

66 U / mL at pH 7.1

A co-polyamino acid / insulin glargine 200 U / mL / insulin lispro 66 U / mL composition is prepared according to the method described above so as to obtain a concentration of insulin glargine Cinsulin glargine = 200 U / mL, a concentration in insulin lispro Cinsulin lispro = 66 U / mL and a concentration of co-polyamino acid C _¥ - polyamino acid (mg / mL). The formulation CB3 'is obtained, the composition of which is presented in the table below: [000741]

Table 3a: Composition CB3 'comprising co-polyamino acid BB15 / glargine / lispro at pH 7

Composition of co-polvamino acid BX2 / insulin olargine 150 U / ml / insulin lisoro 50 U / ml at pH 7.1

According to the preparation process described above, a co-polyamino acid / insulin glargine 150 U / ml / insulin lispro 50 U / ml composition was prepared. The composition is described in the table below:

Table 3b: Composition CB3b comprising co-polyamino acid BX2 / insulin glargine / insulin lispro at pH 7.1.

[000743] Part D - Pre-clinical trial

A pre-clinical study was carried out with the aim of evaluating the pharmacokinetics of insulins after administration of the composition CB3b.

The pharmacokinetic profiles of insulin glargine (sum of the circulating concentration of insulin glargine and its main metabolite, insulin M l) and insulin lispro were obtained for this composition.

Ten animals which have been fasted for 17.5 hours were injected subcutaneously at a dose of 0.67 U / kg of insulin. Blood samples were taken during the 16 hours following administration to describe the pharmacokinetics of insulins. The levels of insulin glargine, insulin M1 and insulin lispro were determined by a specific bioanalysis method.

The median pharmacokinetics profile of glargine (sum of the circulating concentration of insulin glargine and its main metabolite, insulin M l) is presented in Figure 2.

There is a pronounced insulin peak in the first two hours after administration, followed by a very stable basal plateau, until about 13 hours after administration, then a slow decrease in concentration between the two last sampling points.

FIG. 2 represents the median curve of the insulin glargine concentration (also including the insulin M 1 concentration) after administration of the composition CB3b in dogs at a dose of 0.67 U / kg. In this figure, the median values of insulin glargine concentration, in pmol / L, are represented on the ordinate, and the post-injection time, in hours (h), is represented on the abscissa.

[000750]

Part E - Clinical Trials

Example El. Dose linearity at three different doses in type 2 diabetics

[000751] A randomized trial using the euglycemic clamp method was carried out in four crossed periods, and in double blind. This study made it possible to study the linearity of the dose and the safety of a composition CB3 'at three different doses in subjects with type 2 diabetes.

Studied Medicinal Product (IMP)

- Composition CB3 '(BB15 with insulin glargine / insulin lispro 75/25)

CB3 'is a pharmaceutical product which contains the excipient BB15, which dissolves insulin glargine at neutral pH by the formation of a physical complex without covalent bond. This allows insulin glargine and insulin lispro to be mixed in the same formulation.

CB3 'is designed to mimic the physiological secretion of endogenous insulin and to meet the daily needs of patients requiring treatment based on basal and meal insulin.

CB3 'combines insulin glargine and insulin lispro in a 266 solution

U / ml, corresponding to 200 U / ml of insulin glargine and 66 U / ml of insulin lispro, presented in a 2 ml glass vial filled to 1 ml. This high concentration reduces the volumes injected, especially for patients requiring high doses of insulin.

The experimental drug was administered by subcutaneous injection to

0.6, 0.8 or 1.0 U / kg body weight.

In the context of this invention, the results presented are centered on the pharmacokinetics of CB3 'Design and test procedures

This trial is a bicentric, randomized, crossover (4 periods), double-blind, phase 1 trial.

Before any evaluation or procedure, each subject gave his agreement to participate in the study by signing an informed consent form. After confirming the eligibility of the subjects during a selection visit (VI), four dosage visits were conducted (V2 to V5). These visits were separated by a washout period of 6 to 21 days and a follow-up visit concluded the treatment period. For the double-blind dosing period, a random sequence of 4 treatments, that is to say one of the three doses of CB3 '((0.6 u / kg, 0.8 U / kg or 1 , 0 U / kg body weight) or a comparator dose) was assigned to the subject. Subjects arrived at the clinical center on an empty stomach in the morning of each dosing day and remained until the 30-hour euglycemic clamp period and subsequent examinations (vital signs, ECG, local tolerance) were completed. During the clamp procedure, blood samples for the determination of lispro, basal and total plasma insulin concentrations were taken at pre-defined times and the rate of glucose infusion (TIG) over time was recorded for pharmacodynamic analyzes. Subjects attended a follow-up visit between 5 and 12 days after the last dosing visit. The total duration of the study for a subject was between 28 and 102 days.

Goals

The primary objective was to study the dose-proportionality of the PK

(pharmacokinetics) after administration of a single dose of CB3 '(0.6 U / kg, 0.8 U / kg or 1.0 U / kg) during an euglycemic clamp procedure in type 2 diabetics.

The other objectives were:

- to study the dose-response relationship after administration of a dose of CB3 '(0.6

U / kg, 0.8 U / kg or 1.0 U / kg)

- to assess the safety and tolerability of CB3 'up to 30 hours after administration of the dose. Trial population

32 subjects were randomized and completed the trial according to the procedures defined in the trial protocol.

The test population included men and women aged 18 to 70 years, type 2 diabetics for at least 12 months and not suffering from underlying diseases other than diabetes, treated with a dose of total insulin less than 1.2 U / kg / day, an HbAlc level between 6.5% and 9.0% (inclusive), a body mass less than or equal to 125.0 kg and a body mass index (IMG) between 20.0 and 40.0 kg / m ² (included). Subjects with at least one exclusion criterion as defined in the trial protocol were not included in the trial.

Subjects who fulfilled one or more of the exclusion criteria specific to the dosing days (defined in the test protocol) were excluded from the dosing day and their visit was rescheduled. Measures

Mesures_pJiaxmacpclnétjques

To determine the dose-exposure relationship, the PK parameters were calculated from individual profiles of concentrations of insulin lispro, basal insulin (insulin glargine and its metabolites M l and M2) and l total insulin (insulin lispro, basal insulin),) in plasma. All the parameters were calculated on the basis of the actual sampling times. Blood samples were taken at pre-defined times during visits 2 to 5 (V2 to V5), from -2 minutes (pre-dose) to 30 hours.

M easures pha rrnacodmainjciy es.

The PD (pharmacodynamic) response to the administration of the experimental drug was evaluated by the euglycemic clamp method. Blood glucose levels were measured at the clinical site at intervals of approximately 30 minutes. The euglycemic clamp is a validated method in which the glucose infusion rate (TIG) necessary to maintain a predefined and constant glucose concentration in the blood is used as a surrogate marker for the PD effect of a hypoglycemic drug, such as exogenous insulin. Safety measures

The safety evaluation was based on the estimation of the number of adverse events, the number of local tolerance events, and the number of hypoglycemic episodes. Likewise, changes in vital signs, ECG (electro-cardiogram), and standard blood and urine parameters made it possible to assess the safety of the investigational medicinal product.

Statistical method

[000769] A statistical analysis plan was published before the blind data review meeting and the analyzes were carried out according to this plan.

The PK parameters (pharmacokinetics) were calculated from the individual profiles of lispro, basal (glargine, MI and M2) and total (lispro + basal) plasma insulins and the glucodynamic parameters were derived from Individual TIG (glucose infusion rate). The PK parameters were calculated from the baseline adjusted profiles defined as the time 0 value. Basal and total insulin concentrations were calculated by summing the concentrations of the analytes adjusted to the baseline. The dose-exposure PK relationship was evaluated using a so-called “power model” with, in response, the log-transformed parameters and as a fixed effect the log-transformed dose. To assess the PD (pharmacodynamic) dose-response relationship PD of CB3 ', a statistical analysis of the dose-linearity was performed using a regression with the unprocessed parameters as response, the dose and the dose * dose product as data. 5 independent. The dose linearity is demonstrated if the dose * dose estimator is not significantly different from 0. The dose-exposure / response differences in PK / PD parameters for CB3 'were evaluated using a linear mixed model with the clinical site , the dose, the sequence and the period as fixed effects and the subject nested in the sequence as a random effect. The differences between the mean PK / PD0 parameters of CB3 'at the dose of 0.8 U / kg and of the comparator were analyzed with a linear mixed model with the clinical site, the treatment, the sequence and the period as fixed effects and the subject nested in the sequence as a random effect. In the case where the effect of the clinical site was not significant, the mixed models were applied without the clinical site as a fixed effect. Safety parameters were analyzed5 only by descriptive statistics.

Results

DemoqraphiciuesJ tial characteristics

The descriptive statistics of demography and other initial characteristics are presented for the 32 subjects randomized in Table 24.

All subjects were Caucasian, 8 (25.0%) were women and 24 (75.0%) were men. At the start of the study, subjects had a history of type 2 diabetes of 13.2 ± 6.69 years (mean ± SD)

5 Table 24: initial demographic characteristics

Safety results

CB3 ', tested at doses of 0.6, 0.8 and 1.0 U / kg, was safe and well tolerated, 0 painless, no reaction at the injection site, and no symptoms d local irritation. None of the vital signs or ECG records, physical examination results, and standard blood and urine parameters raised any safety concerns. PK / PD

Comparison of the average pharmacokinetics of basal insulin (sum of the concentrations of insulin glargine and its metabolites M l and M2) after subcutaneous administration of CB3 'at 0.8 U / kg in patients type 2 diabetics (n = 31) is presented in the following table.

Table 25: PK parameters (mean (CV%)) of basal insulin (sum of the concentrations of insulin glargine and its metabolites M l and M2) after subcutaneous administration of CB3 'at 0.8 U / kg in type diabetic patients

2 (n = 31)

CB3 'has a proportional dose / exposure ratio for doses of 0.6, 0.8 and 1.0 U / kg. In line with these PK results, CB3 'shows a linear dose-response relationship. CB3 'basal insulin exposure is also dose-proportional. The data presented in the table above and in FIG. 1 show that the early post-dose periods between 0 and 30 minutes and between 0 and 1 hour are characterized by a rapid increase in basal insulin concentrations which is comparable over the dose range.

This surprisingly shows that CB3 'leads to a pronounced peak of basal insulin (insulin glargine + Ml + M2) during the early post-injection period contrasting with the flat profile typical of Lantus®, and leading to exposure significantly higher during the first hour post-dose (AUCbas 0-lh). The typical flat profile of insulin glargine is shown in application WO2011144673 by Sanofi, showing the flat PK of insulin glargine at 100 U / ml and that even flatter of insulin glargine at 300 U / ml , in humans.

Claims

127

5 1, Composition in the form of an aqueous solution for injection, the pH of which is between 6.0 and 8.0, comprising at least:

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

b) a co-polyamino acid carrying carboxylate charges and radicals

10 hydrophobic Hy, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic radicals Hy being of following formula X:

Formula X

15 in which

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

;

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

XI or XI ':

O

JL H

G— N— * Form XI Form CG

25 GpA is chosen from the radicals of formula VIII

Formula VIII In which A 'is chosen from the radicals of formula VIII', VIII "or VIII"'

Form VIII 'Form VIII "Form VIII'"

-GpL is chosen from the radicals of formula XII

Formula XII,

GpC is a radical of formula IX:

b is an integer equal to 0 or 1;

if e is different from 0 then at least one of the g, h or I is different from 0; and if a = 0 then 1 = 0;

A, Ai, A2 and A3, which are identical or different, are linear or branched alkyl radicals, and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring, comprising from 1 to 8 carbon atoms; - B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;

^■ 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).

- 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 - CON H2 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 the PLG:

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

the free carboxylic acid functions being in the form of an alkali cation salt chosen from the group consisting of IMa ⁺ and K ⁺ , for use in a method of treating diabetes and controlling blood sugar, characterized in that the basal insulin has a prandial effect and a basal effect.

2. Composition according to claim 1, characterized in that the onset of the meal effect is obtained within a period of between 0 and 30 minutes after administration.

3. Composition according to any one of claims 1 to 2, characterized in that the prandial effect originating from basal insulin is characterized by a marked peak in basal insulin within 0-4 hours after administration.

4. Composition according to any one of claims 1 to 3, characterized in that the prandial effect originating from basal insulin is characterized by an area under the curve of the basal insulin concentration between 0 and 30 min (AUCbas0- 30) greater than an identical composition free of carrier co-polyamino carboxylates fillers and hydrophobic radicals Hy or a composition of Lantus ^®.

5. Composition according to any one of claims 1 to 2, characterized in that the basal effect is obtained within a period of between 15 minutes and at least 12 hours after administration

6. Composition according to any one of claims 1 to 5, characterized in that it further comprises a mealtime insulin.

7. Composition according to any one of claims 1 to 6, characterized in that it further comprises a gastrointestinal hormone.

8. Composition according to any one of claims 1 to 7, characterized in that it is administered 2 times a day.

9. Composition according to any one of claims 1 to 7, characterized in that it is administered 1 time per day.

10. 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

11. 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.

12. 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.

13. Composition according to any one of the preceding claims, characterized in that the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 40 mg / ml.

14. 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.

15. 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.

16. Composition according to any one of claims 4 to 15, characterized in that in total it comprises between 40 and 500 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is understood between 5.8 and 8.5.

17. Composition according to any one of claims 4 to 15, 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.

18. Composition according to any one of the preceding claims, characterized in that it also comprises a gastrointestinal hormone.

19. Composition according to claim 18, characterized in that the gastrointestinal hormone is chosen from the group consisting of exenatide, liraglutide, lixisenatide, albiglutide and dulaglutide, their analogs or derivatives and their pharmaceutically acceptable salts.

20. Composition according to any one of claims 18 to 19, characterized in that the gastrointestinal hormone is dulaglutide, its analogs or derivatives and their pharmaceutically acceptable salts.

21. Composition according to any one of claims 18 to 19, characterized in that the gastrointestinal hormone is exenatide, its analogs or derivatives and their pharmaceutically acceptable salts.

22. Composition according to any one of claims 18 to 19, characterized in that the gastrointestinal hormone is liraglutide, its analogs or derivatives and their pharmaceutically acceptable salts.

23. Composition according to any one of claims 18 to 19, characterized in that the gastrointestinal hormone is lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts.

24. Composition according to any one of claims 18 to 23, characterized in that the concentration of gastrointestinal hormone is in the range of 0.01 to 10 mg / ml.

25. Composition according to any one of claims 18, 19 or 21, 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.

26. Composition according to any one of claims 18, 19 or 22 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.