FR3074680A1 - COMPOSITIONS IN THE FORM OF AQUEOUS INJECTABLE SOLUTION COMPRISING AMYLINE, AMYLINE RECEPTOR AGONIST OR AMYLINE ANALOGUE AND CO-POLYAMINOACID - Google Patents

Abstract

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) amylin, an amylin receptor agonist or a amylin analogue; b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid being constituted by glutamic or aspartic units and said hydrophobic radicals Hy being of formula I below: characterized in that the composition does not comprise any a basal insulin whose isoelectric point pI is between 5.8 and 8.5. It also relates to a composition characterized in that it further comprises prandial insulin.

Description

COMPOSITIONS IN THE FORM OF AN AQUEOUS INJECTABLE SOLUTION COMPRISING AMYLINE, AN AMYLINE RECEPTOR AGONIST OR AN AMYLINE ANALOG AND A CO-POLYAMINOACID [0001] The invention relates to injection therapy of amylin, d amylin receptor agonist or amylin analog to treat diabetes.

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 amylin, an agonist at the amylin receptor or a analog of amylin and a copolyamino acid carrying carboxylate charges and hydrophobic radicals according to the invention and compositions further comprising an insulin (excluding basal insulins whose isoelectric point pi is between 5.8 and 8.5 ). The invention also relates to pharmaceutical formulations comprising the compositions according to the invention. Finally, the invention also relates to a use of the copolyamino acids carrying carboxylate charges and of hydrophobic radicals according to the invention for stabilizing compositions of amylin, of amylin receptor agonist or of amylal analog thus as amylin, amylin receptor agonist or amylin analog compositions further comprising insulin.

Type 1 diabetes is an autoimmune disease leading to the destruction of beta cells in the pancreas. These cells are known to produce insulin, the main role of which is to regulate the use of glucose in peripheral tissues (Gerich 1993 Control of glycaemia). Consequently, patients with type 1 diabetes suffer from chronic hyperglycemia and must administer exogenous insulin in order to limit this hyperglycemia. Insulin therapy has made it possible to drastically change the life expectancy of these patients. However, the glycemic control provided by exogenous insulin is not optimal, especially after taking a meal. This is related to the fact that these patients produce glucagon after taking a meal, which leads to the destocking of part of the glucose stored in the liver, which is not the case in the healthy person. This glucagon-mediated glucose production exacerbates the problem of regulating blood sugar in these patients.

It has been shown that amylin, another hormone produced by beta cells in the pancreas and therefore also deficient in type 1 diabetic patients, plays a key role in the regulation of postprandial blood sugar. Amylin, also known as the "islet amyloid polypeptide" or IAPP, is a 37 amino acid peptide that is co-stored and co-secreted with insulin (Schmitz 2004 Amylin Agonists). This peptide is described to block the production of glucagon by the alpha cells of the pancreas. Thus, insulin and amylin have complementary and synergistic roles, since insulin makes it possible to reduce the concentration of glucose in the blood whereas amyline makes it possible to reduce the entry of endogenous glucose into the blood by inhibiting the production (secretion) of endogenous glucagon.

This problem of regulating postprandial glycemia is fairly similar for patients with type 2 diabetes treated with insulin insofar as their disease has led to a very significant loss of their beta cell mass and therefore, their ability to produce insulin and amylin.

Human amylin has properties which are not compatible with pharmaceutical requirements in terms of solubility and stability (Goldsbury CS, Cooper GJ, Goldie KN, Muller SA, Saafi EL, Gruijters WT, Misur MP, Engel A , AeBIU, Kistler J: Polymorphie fibrillar assembly of human amylin. J Struct Biol 119: 17-27, 1997). Amylin is known to form amyloid fibers which lead to the formation of plaques which are insoluble in water. Although being the natural hormone, it was necessary to develop an analog in order to solve these solubility problems.

The physico-chemical properties of amylin thus make its use impossible: amylin is only stable for about fifteen minutes at acidic pH, and less than a minute at neutral pH.

The company Amyiin has developed an analog of amylin, pramlintide, to overcome the lack of stability of human amylin. This product marketed under the name of Symlin was approved in 2005 by the FDA for the treatment of type 1 and type 2 diabetics. It must be administered subcutaneously three times a day, in the hour preceding the meal in order to improve postprandial blood sugar control. This peptide is formulated at acidic pH and is described to shine when the pH of the solution is higher than 5.5. Variants of analogs are described in US Patent 5,686,411.

This analog is thus not satisfactory in terms of stability when a formulation at neutral pH is envisaged.

To date, there is no way to stabilize human amylin to make it a pharmaceutical product. However, it would be advantageous for patients to have access to the human form of this physiological hormone. It would also be advantageous to be able to formulate a neutral pH amylin receptor analog or agonist.

In addition, there would be an advantage in being able to mix amyline, an analogue of amylin, or an amylin receptor agonist, with a mealtime insulin in aqueous solution since these two products are to be administered before the meal. This would also mimic physiology since these two hormones are co-secreted by beta cells in response to a meal to improve control of postprandial blood sugar.

However, taking into account the fact that the prandial insulin solutions have a pH close to neutral for reasons of chemical stability, it is not possible to obtain an aqueous solution meeting the pharmaceutical requirements in terms of solubility and stability.

For this reason, patent application US2016 / 001002 from the company ROCHE describes a pump containing two separate reservoirs in order to make possible the co-administration of these two hormones with a single medical device. However, this patent does not solve the problem of mixing these two hormones in solution which would make it possible to administer them with conventional pumps already on the market which contain only one reservoir.

Patent application W02013067022 from the company XERIS provides a solution to the problem of the stability of amylin and its compatibility with insulin by using an organic solvent instead of water. The absence of water seems to solve the stability problems but the use of an organic solvent poses safety problems of chronic use for diabetic patients and also problems of compatibility with the usual medical devices, at the level of the tubes. , seals and plasticizers used.

Patent application WO2007104786 from the company NOVO NORDISK describes a method for stabilizing a pramlintide solution, which is an analogue of amylin, and of insulin by adding a phospholipid, a derivative of glycerophosphoglycerol, in particular dimyristoyl glycerophosphoglycerol (DMPG). However, this solution requires the use of large quantities of DMPG which can pose a problem of local tolerance.

To the knowledge of the plaintiff, i! there is no satisfactory means which makes it possible to combine in aqueous solution a mealtime insulin and human amylin, an amylin receptor agonist or an analog of amylin in order to be able to be administered with conventional devices.

The acid formulation pH and rapid fibrillation are obstacles to obtaining a pharmaceutical formulation with neutral pH based on amylin and pramlintide, but also a brake in combining amylin or pramlintide with other pharmaceutical ingredients. active, in particular peptides or proteins.

The Applicant has noticed that, surprisingly, the copolyamino acids according to the invention stabilize compositions of amylin, amylin receptor agonist or amylin analog at a pH between 6 and 8 In fact, compositions comprising amylin, an amylin receptor agonist or an amylin analog in combination with a co-polyamino acid according to the invention exhibit increased stability over time, which is great interest in pharmaceutical development.

The Applicant has also found that the co-polyamino acids according to the invention also make it possible to obtain a composition comprising prandial insulin and amylin, agonist at the amylin receptor or amylin analog, said composition being clear and having improved fibrillation stability.

A conventional method for measuring the stability of proteins or peptides consists in measuring the formation of fibrils using Thioflavin T, also called ThT. This method makes it possible to measure, under temperature and stirring conditions which allow the phenomenon to accelerate, the lag time before the formation of fibrils by measuring the increase in fluorescence. The compositions according to the invention have a latency time before the formation of fibrils significantly greater than that of amylin, of an agonist at the amylin receptor or of an amylin analog at the pH of interest.

The compositions according to the invention have physical, and possibly chemical, stability, satisfactory at the desired pH.

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) amylin, an amylin receptor agonist or an amylin analog;

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

• 4g _p r) 4gpaÙgpc) ^ra P Formula I in which

GpR is a radical of formulas II or ΙΓ: O H H He h * —N ~ R — N ~ * π or * - -1L-R _N * _n ,.

GpA is a radical of formulas III or ΙΙΓ:

*

* HN

III or

H

A — N— * ni ';

- GpC is a radical of formula IV:

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

a is an integer equal to 0 or 1;

b is an integer equal to 0 or 1;

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

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

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

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

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

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

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

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

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

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

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

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

o if p is equal to 2, x is between 9 and 15 (9 <x <15), the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <i <0 , 5;

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

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

characterized in that the composition does not include a basal insulin whose isoelectric point pi is between 5.8 and 8.5.

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

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

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

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

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 and European pharmacopoeias concerning 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.

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

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

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

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

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

* 4gpR) 4gpA) —GpC ^ra formula V

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II in which R is a polyether radical chosen from the group consisting of radicals

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

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

* ★ * * * h ₃ c ^ J ch ₃ ch ₃ i * * τ ★ * ★ * ®η ₃ h ₃ c ^x CH ₃ * h ₃ c ^ * H ₃ C ^ * ^K ch ₃

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc below. after 5 represented:

/ 0 \ X ^iJJ -Xf · Formula IVa Formula IVb ΧχΜγ Formula IVc

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

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

OO v _Cx \ _N Formula IVd PO y_c _x Formula IVe Λ-Λ. Formula IVf

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV in which b = 1 is chosen from the group consisting of radicals in which B 10 is an amino acid residue selected from the group consisting of radicals represented by the formulas below:

* * * * * * h ₃ cJ ch ₃ ★ * * * * * L, η ₃ ο ^ ch ₃ * * H, C ^ * * * *

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

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

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

In one embodiment, its composition is characterized in that Se hydrophobic radicaS is a radica! of formula V in SaqueSIe the radicaS GpC of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the aSkyles radicals comprising between 11 and 14 carbon atoms. In one embodiment, its composition is characterized in that radica! hydrophobic is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:

* x = ll : * ch ₃ x = 13

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

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

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

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

x = 17 [00074] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.

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

In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which a - 1 and p = 2, represented by the following formula VI:

'- (GpR V- GpA— (GpC) ^{r 2} Formula VI in which

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the composition is characterized in that the ether radical is * [00095] In one embodiment, the composition is characterized in that the

hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or ΙΓ, in which R is a polyether radical.

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

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula III is chosen from the group consisting of the radicals of formulas Ilia and Illb below

Ilia formula

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

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

* Ύ ° ίη Ί k PL / ^nh L / C _x A ⁵ q Formula IVa Formula IVb Formula IVc

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

[000102] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula

IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, corresponding respectively to the formulas IVd, IVe, and IVf below represented: __________________________________

-y- Formula IVd * y ° y-c, ô Formula IVe O O -yy. Formula IVf

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

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

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

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

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

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

x = 9 * - x = ll * X ch ₃ x = 13

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

x = 15 [000112] In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII below:

Hy formula VII in which, • D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, in which r = 1 and GpR is a radical of Formula II, • Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI in which r = 0 or r = 1 and GpR is a radical of Formula ΙΓ, or a radical chosen from the group consisting of an H, a linear acyl group at C2 to CIO, a branched acyl group at C3 to CIO, a benzyl, a terminal "amino acid" unit and a pyrogututate, • R2 is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI in which r = 1 and GpR is a radical of Formula II, or an identical or different radical -NR'R, R 'and R being chosen from the group consisting of H, linear or branched or cyclic C2 to CIO alkyl, b enzyl and said R 'and R alkyl which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, N and S, • X represents an H or a cationic entity chosen from the group comprising metallic cations;

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

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

The term “statistical co-polyamino acid” means a co-polyamino acid carrying carboxyl charges and at least one hydrophobic radical, a co-polyamino acid of formula VIIa.

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 VII, in which Ri = R'i and R2 = R '2, of the following formula Vlla:

in which,

- m, η, X, D and Hy have the definitions given above,

RT is a radical chosen from the group consisting of an H, a linear C2 to CIO acyl group, a branched C3 to CIO acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate,

- RT is 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, benzyl and said R' and R alkyls which can form together one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, N and S.

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

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

Formula Vllb 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 I, V or VI.

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

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

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VHb in which R2 is a hydrophobic radical of formula I, V or VI in which r = 1 and GpR is of Formula II.

In one embodiment, the composition is characterized in that Ri is a radical chosen from the group consisting of a linear acyl group at C2 to Cio, a branched acyl group at C3 to Cio, a benzyl, a unit " amino acid 'terminal and a pyroglutamate.

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the Cx radical comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.05.

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

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

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

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

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

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

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

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

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

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

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

Amylin, or islet amyloid polypeptide (IAPP), is a peptide hormone with 37 residues. It is co-secreted with insulin from pancreatic beta cells in the ratio of about 100: 1. Amylin plays a role in glycemic regulation by stopping the secretion of endogenous glucagon and slowing gastric emptying and promoting satiety, thus reducing postprandial glycemic excursions in blood glucose levels.

IAPP is treated from a coding sequence of 89 residues. The amyloid Proislet polypeptide (proIAPP, proamyline, proislet protein) is produced in pancreatic beta cells (beta cells) as a pro-peptide of RSO 67 amino acids, 7404 Dalton, and undergoes post-translational modifications including cleavage of protease to produce amylin.

In the present application, the amylin as mentioned refers to the compounds described in US patents 5,124,314 and US 5,234,906.

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 amino acid residues constituting the primary sequence have been substituted with d other amino acid residues 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 the case of amylin, an analog may for example be derived from the primary amino acid sequence of amylin by substituting one or more natural or non-natural or peptidomimetic amino acids.

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 analog, that is to say a peptide or a protein which has been modified by creation of covalent bonds, to introduce substituents of the non-amino acid type.

An agonist at the amylin receptor refers to a compound which mimics one or more characteristics of the activity of amylin.

[000159] Amylin derivatives are described in the article Yan et al., PNAS, vol. 103, no 7, p 2046-2051, 2006.

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

Analogs of amylin are described in US patents 5,686,411, US 6,114,304 or even US 6,410,511.

In one embodiment, the composition is characterized in that the amylin analog is pramlintide (Symlin®) sold by the company ASTRAZENECA AB.

In one embodiment, the molar ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between

1.5 and 75.

In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog molar ratios are between 1.8 and 50.

In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog molar ratios are between and 35.

In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog molar ratios are between

2.5 and 30.

In one embodiment, the molar ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between and 30.

In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog molar ratios are between

3.5 and 30.

In one embodiment, the molar ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between and 30.

In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue molar ratios are between and 30.

In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog molar ratios are between 7 and 30.

In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue molar ratios are between 9 and 30.

In one embodiment, amylin are between 3 and 75.

In one embodiment, amylin are between 7 and 50.

In one embodiment, amylin are between 10 and 30.

In one embodiment, amylin are between 15 and 30.

In one embodiment, pramlintide are between 1.5 and 75.

In one embodiment, pramlintide are between 2 and 50.

[000179] In one embodiment, pramlintide are between 3 and 30.

In one embodiment, pramlintide are between 4 and 30.

In one embodiment, pramlintide are between 5 and 30.

In one embodiment, pramlintide are between 8 and 30.

In one embodiment,

the ratios molars the ratios molars the ratios molars the ratios molars the ratios molars the ratios molars the ratios molars the ratios molars the ratios molars the ratios molars the ratios molars

co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / co-polyamino acid / pramlintide are included between 10 and 30.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between

1.5 and 150.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 1.8 and 100.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 2 and 70.

In one embodiment, the hydrophobic Hy / amylin radical molar ratios, agonist at the amylin receptor or amylin analog are between

2.5 and 60.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between and 60.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between

3.5 and 60.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between and 60.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between and 60.

In one embodiment, the hydrophobic Hy / amylin radical molar ratios, agonist at the amylin receptor or amylin analog are between 7 and 60.

In one embodiment, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 9 and 60.

an embodiment, [000194] In amyline are between 5 and 60. In one embodiment, amyline are between 10 and 60.

In one embodiment, amylin are between 15 and 60.

In one embodiment, pramlintide are between 1.5 and 60.

In one embodiment, pramlintide are between 2 and 60.

In one embodiment, pramlintide are between 3 and 60.

In one embodiment, pramlintide are between 4 and 60.

In one embodiment, pramlintide are between 5 and 60.

[000202] In one embodiment, pramlintide are between 8 and 60.

In one embodiment, the the the the the the the the the the the ratios ratios ratios ratios ratios ratios ratios ratios ratios ratios ratios molar molar molar molar molar molar molar molar molar molar molar molar radical radical radical radical radical radical radical radical radical hydrophobic radical Hy / hydrophobic Hy / hydrophobic Hy / hydrophobic Hy / hydrophobic Hy / hydrophobic Hy / hydrophobic Hy / hydrophobic Hy / hydrophobic Hy / hydrophobic Hy / pramlintide are between 10 and 60.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 1.0 and 70.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist to the amylin receptor or amylin analog are between 1.2 and 45.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist to the amylin receptor or amylin analog are between 1.3 and 30.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist to the amylin receptor or amylin analog are between 1.7 and 27.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist to the amylin receptor or amylin analog are between 2.0 and 27.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 2.3 and 27.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist to the amylin receptor or amylin analog are between 2.7 and 27.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 3.3 and 27.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 4.7 and 27.

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist to the amylin receptor or amylin analog are between 6.0 and 27.

In one embodiment, the ratios mass co- polyamino acid / amyline are between 2.0 and 67. In one embodiment, polyamino acid / amylin are between 4.7 and 27. the ratios mass co- In one embodiment, polyamino acid / amylin are between 6.7 and 27. the ratios mass co -

In one embodiment, the copolyamino acid / amylin mass ratios are between 10 and 27.

In one embodiment, pramlintide are between 1.0 and 57.

In one embodiment, pramlintide are between 1.3 and 45.

In one embodiment, pramlintide are between 2.7 and 27.

In one embodiment, pramlintide are between 3.3 and 27.

In one embodiment, pramlintide are between 5.3 and 27.

In one embodiment, pramlintide are between 6.7 and 27.

co-polyamino acid mass ratios / co-polyamino acid mass ratios / co-polyamino acid mass ratios / co-polyamino acid mass ratios / co-polyamino acid mass ratios / co-polyamino acid mass ratios / [000224] In one embodiment , the composition is characterized in that it further comprises insulin.

In one embodiment, the composition is characterized in that the insulin is a mealtime insulin. Prandial insulins are soluble at pH 7.

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 insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.

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

The so-called fast acting prandial insulins are insulins which are obtained by recombination and whose primary sequence has been modified to reduce their action time.

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

[000233] 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.

The units recommended by the pharmacopoeias for insulins are presented in table 40 below with their correspondences in mg:

Insulin Pharmacopoeia EP 8.0 (2014) US Pharmacopoeia - USP38 (2015) aspart 1U = 0.0350 mg insulin aspart 1 USP = 0.0350 mg insulin aspart lispro 1U = 0.0347 mg insulin lispro 1 USP = 0.0347 mg insulin lispro human 1IU = 0.0347 mg of human insulin 1 USP = 0.0347 mg human insulin

Table 40: Units recommended by the pharmacopoeias for insulins [000237] In the case of insulin glulisine, 100U = 3.49 mg of insulin glulisine (according to Annex 1 - Summary of product characteristics relating to ADIPRA®).

However in the following text U is systematically used interchangeably for the amounts and concentrations of all insulins. The respective values corresponding in mg are those given above for values expressed in U, UI or USP.

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is between 240 and 3000 pM (40 to 500 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is between 600 and 3000 pM (100 to 500 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is between 600 and 2400 pM (100 to 400 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is between 600 and 1800 pM (100 to 300 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is between 600 and 1200 pM (100 to 200 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 600 pM (100 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 1200 pM (200 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 1800 pM (300 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 2400 pM (400 U / ml).

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 3000 μΜ (500 U / ml).

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog receptor molar ratios are between 1.5 and 75.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog molar ratios are between 1.8 and 50.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 2 and 35.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 2.5 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 3 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog receptor molar ratios are between 3.5 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 4 and 30.

In one embodiment comprising prandial insulin, the molar ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 5 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 7 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 9 and 30.

In an embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios are between 5 and 75.

In an embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios are between 10 and 50.

In an embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios are between 15 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 1.5 and 75.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 2 and 50.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 3 and 30.

[000265] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 4 and 30.

[000266] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 5 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 8 and 30.

[000268] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 10 and 30.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 1.5 and 150.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 1.8 and 100.

In one embodiment comprising prandial insulin, the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 2 and 70.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amyiine molar ratios, agonist at the amylin receptor or amylin analog are between 2.5 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 3 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin radical ratios, agonist at the amylin receptor or amylin analog are between 3.5 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 4 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical molar ratios Hy! amylin, amylin receptor agonist or amylin analog are between 5 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 7 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 9 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios are between 5 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios are between 10 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin molar ratios are between 15 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 1.5 and 60.

[000283] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 2 and 60.

[000284] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 3 and 60.

[000285] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 4 and 60.

[000286] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 5 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 8 and 60.

In one embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 10 and 60.

In one embodiment comprising prandial insulin, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 1.0 and 70.

In one embodiment comprising prandial insulin, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 1.2 and 45.

In one embodiment comprising prandial insulin, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 1.3 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog receptor mass ratios are between 1.7 and 27.

In one embodiment comprising prandial insulin, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 2.0 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist to receptor for amylin or amylin analog mass ratios are between 2.3 and 27.

In an embodiment comprising prandial insulin, its co-polyamino acid / amylin mass ratios, agonist at the amylin receptor or amylin analog are between 2.7 and 27.

In one embodiment comprising prandial insulin, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog are between 3.3 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog receptor mass ratios are between 4.7 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog receptor mass ratios are between 6.0 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin mass ratios are between 3.3 and 67.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin mass ratios are between 6.6 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin mass ratios are between 10 and 27.

In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 1.0 and 67.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 1.2 and 45.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 1.3 and 27.

[000305] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 1.7 and 27.

In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 2.0 and 27.

In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 2.3 and 27.

In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 2.7 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 3.3 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 4.7 and 27.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide mass ratios are between 6.0 and 27.

In addition, it is particularly advantageous to combine amylin, an agonist at the amylin receptor or an amylin analog, in combination or not with a mealtime insulin, with GLP-1, GLP analogs -1, GLP-1 receptor agonists, these are commonly called GLP-1 RA. This allows in particular to potentiate the effect of insulin and is recommended in certain types of diabetes treatment.

In one embodiment, GLP-1, analogs of GLP-1, or GLP-1 RA are said to be "fast". The term "rapid" means GLP-1, analogs of GLP-1, or GLP-1 RA, the apparent elimination half-life after subcutaneous injection in humans is less than 8 hours, in particular less 5 hours, preferably less than 4 hours or even less than 3 hours, such as exenatide and lixisenatide.

In one embodiment, GLP-1, GLP-1 analogs, or GLP-1 RA are chosen from the group consisting of exenatide or Byetta® (ASTRAZENECA), lixisenatide or Lyxumia® ( SANOFI), their analogs or derivatives and their pharmaceutically acceptable salts.

In one embodiment, GLP-1, analog of GLP-1, or GLP-1 RA is exenatide or Byetta®, its analogs or derivatives and their pharmaceutically acceptable salts.

In one embodiment, GLP-1, analog of GLP-1, or GLP-1 RA is lixisenatide or Lyxumia®, its analogs or derivatives and their pharmaceutically acceptable salts.

In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in the range of 0.01 to 1.0 mg per 100 U of insulin.

In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.01 to 0.5 mg per 100 U of insulin.

In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 100 U of insulin.

In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 100 U of insulin.

In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.2 mg per 100 U of insulin.

In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.15 mg per 100 U of insulin.

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 per 100 U of insulin.

In one embodiment, the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.01 to 0.5 mg per 100 U of insulin.

In one embodiment, the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 100 U of insulin.

In one embodiment, the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 100 U of insulin.

In one embodiment, the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.2 mg per 100 U of insulin.

In one embodiment, the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is from 0.04 to 0.15 mg per 100 U of insulin.

In one embodiment, the compositions according to the invention are produced by mixing amylin solutions and commercial solutions of GLP-1, of GLP-1 analog or of agonist of GLP receptors- 1 RA in volume ratios in the range 10/90 to 90/10 in the presence of a co-polyamino acid.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 500 μΜ per 100 U of insulin.

In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 0 and 400 μΜ per 100 U of insulin.

In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration between 0 and 300 μΜ per 100 U of insulin.

In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration between 0 and 200 μΜ per 100 U of insulin.

In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration of between 0 and 100 μΜ per 100 U of insulin.

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

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

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

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

In one embodiment, the buffer is sodium phosphate.

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

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 also 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 may 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.

[000352] In the case of local and systemic releases, the modes of administration envisaged are by the intravenous, subcutaneous, intradermal or intramuscular route. [000353] The transdermal, oral, nasal, vaginal, ocular, oral, pulmonary administration routes are also envisaged.

The invention also relates to a pump, implantable or transportable, comprising a composition according to the invention.

The invention also relates to the use of a composition according to the invention intended to be placed in a pump, implantable or transportable.

The invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising amylin, an agonist at the amylin receptor or an amylin analog and a co-polyamino acid according to the invention.

The invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising amylin, an agonist at the amylin receptor or amylin analog, a co-polyamino acid according to the invention and a GLP-1, an analog of GLP-1 or a GLP-1 RA, as defined above.

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising amylin, an agonist at the amylin receptor or an amylin analog and a co-polyamino acid according to the invention.

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising amylin, an agonist at the amylin receptor or an amylin analog, a co-polyamino acid according to the invention and a mealtime insulin, as defined above.

The invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising amylin, an amylin receptor agonist or an amylin analog and a co-polyamino acid according to the invention.

The invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising amylin, an agonist at the amylin receptor or an amylin analog, a co-polyamino acid according to the invention and a mealtime insulin, as defined above.

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

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

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 amylin, of an agonist at the amylin receptor or of an analogue of amylin, and a copolyamino 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 amylin, of an agonist at the amylin receptor or of an analogue of amylin, prandial insulin, 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 mealtime insulin and copolyamino acid is concentrated by ultrafiltration.

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.

In one embodiment, the compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an agonist at the amylin receptor or the like of amylin but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals.

In one embodiment, the compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an agonist at the amylin receptor or the like of amylin in combination with an insulin but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy.

In one embodiment, the compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an agonist at the amylin receptor or the like amylin in combination with GLP-1, a GLP1 analog or a GLP-1 receptor agonist, but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals.

In one embodiment, the compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an agonist at the amylin receptor or the like amylin in combination with insulin and GLP-1, a GLP-1 analogue or a GLP-1 receptor agonist, but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals.

The invention also relates to the use of a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals to stabilize a composition comprising amylin, an amylin receptor agonist or an amylin analog.

The invention also relates to the use of a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals for stabilizing a composition comprising amylin, an amylin receptor agonist or an amylin analog and a mealtime insulin, and optionally a GLP-1, a GLP-1 analog or a GLP-1 receptor agonist.

The invention relates to a composition stabilization method comprising amylin, an amylin receptor agonist or an amylin analog or a composition stabilization method comprising amylin, a receptor agonist amylin or an amylin analog and a mealtime insulin, and optionally a GLP-1, a GLP-1 analog or a GLP1 receptor agonist.

The following examples illustrate, without limitation, the invention.

Partie_A

AA: Synthesis of hydrophobic molecules in which p = 1 [000376] The hydrophobic radicals are represented in the following table by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.

No. STRUCTURE OF THE HYDROPHOBIC MOLECULE BEFORE GRAFTING ON THE COPOLYAMINOACID IAA ® _O ^ C ₁₅ H ₃₁ AA2 .NK X. / H ₂ NYN q'X ^ ' ^C 13 ^H 26 AA3 ⁰ _ο · Λ-0 ₁₅ η ₃₁ AA4 ^v o | 0 ^ J ^ C ₁₅ H ₃₁ AA5 ^ nh ₂ % ^ ^C 15 ^H 31 H ₂ rr nh t ° A>

AA 6 H ₂ N X \ X ¹ 1 Z A / n ^N 0 / A. cr C17H35 AA7 ^H 2 ^N \ ^ 0 ' χ ^, Χ 0 0 w ha vs / ^{C 7:39} p.m. AA8 ΓΛ h, N '-' ^NH Λ) NOT ¥ 0 Λγ Ί NH Ù15 ^H t 31 O h ₃ c ^ / ch ₃ AA 9 X not 'NOT II 0 NH / ^CllH ï 23 O q AA10 .NH X / > h ₂ n ^ χ N He \ ο A o ^z X ₃ H ₂₇ AA11 H ₂ N '(AT n x \ / v .NH T Q 0 q / ^^ Ci3 ^H 27

Table ΙΑ: list and structures of hydrophobic molecules synthesized according to the invention.

Example AAI: AAI molecule

Molecule Al: product obtained by the reaction between palmitoyl chloride and Lproline.

A solution of L-proline (10.6 g, 92.1 mmol) in 1 N aqueous sodium hydroxide (230 mL; 230 mmol) is added dropwise for 90 minutes a solution of palmitoyl chloride ( 23.0 g, 83.7 mmol) in acetone (167 mL). After 14 h of stirring at room temperature, the heterogeneous mixture is cooled to 0 ° C., then filtered through a frit to give a white solid which is washed with water (2 x 100 mL) then diisopropyl ether (100 mL) . The solid is dried under reduced pressure. The solid is then dissolved at reflux in 200 ml of water and then 8 ml of a hydrochloric acid solution at 37% are added to obtain a pH = 1. The opalescent reaction medium is then cooled to 0 ° C. The precipitate obtained is filtered on a frit and then washed with water (5 x 50 mL) until filtrates of physiological pH between 6.0 and 8.0 are obtained, then they are dried in an oven at 50 ° C under empty overnight. The product is purified by recrystallization from diisopropyl ether. A white solid is obtained.

Yield: 22.7 g (77%).

^X H NMR (CDCl _3, ppm): 0.88 (3H); 1.19-1.45 (24H); 1.58-1.74 (2H); 1.88-2.14 (3H); 2.15-2.54 (3H); 3.47 (1H); 3.58 (1H); 4.41 (0.1H); 4.61 (0.9H) 6.60-8.60 (1H).

Molecule, A2__L product obtained by reaction between the molecule Al and Bocethylenediamine.

To a solution of molecule Al (75.1 g, 212.4 mmol) in 1500 ml of chloroform are added successively and at room temperature N, Ndiisopropylethylamine (DIPEA) (68.8 g, 532.3 mmol ), 1-hydroxybenzotriazole (HOBt) (37.1 g, 274.6 mmol) then N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) (53.1 g, 277.0 mmol). After 15 minutes of stirring at room temperature, a solution of Boc-ethylenediamine (Boc-ethylenediamine) (37.6 g, 234.7 mmol) in 35 ml of chloroform is added. After 18 h of stirring at room temperature, a 0.1 N HCl solution (2.1 L), then a saturated NaCl solution (1 L) are added. The phases are separated then the organic phase is washed successively with a 0.1 N HCl solution / saturated NaCl (2.1 L / l L), a saturated NaCl solution (2 L), a saturated NaHCO3 solution (2 L), then a saturated NaCl solution (2 L). The organic phase is dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained is purified by trituration in diisopropyl ether (3 x 400 mL), to give a solid after drying under vacuum at 40 ° C.

Yield: 90.4 g (86%).

Ή NMR (CDCh, ppm): 0.88 (3H); 1.20-1.37 (24H); 1.44 (9H); 1.54-1.70 (2H); 1.79-1.92 (1H); 1.92-2.04 (1H); 2.03-2.17 (1H); 2.17-2.44 (3H); 3.14-3.36 (4H); 3.43 (1H); 3.56 (1H); 4.29 (0.1 H); 4.51 (0.9 H); 4.82 (0.1H); 5.02 (0.9H); 6.84 (0.1H); 7.22 (0.9H).

AAI molecule [000379] A solution of molecule A2 (20.1 g, 40.5 mmol) in 330 mL of dichloromethane is added dropwise and at 0 ° C a solution of 4 M hydrochloric acid in dioxane (100 mL, 400 mmol). After 3 h 30 min of stirring at room temperature, the solution is concentrated under reduced pressure. The residue is purified by flash chromatography (methanol, dichloromethane) to give a white solid of molecule AAI in the form of the hydrochloride salt.

Yield: 16.3 g (93%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.07-1.40 (24H); 1.49-1.63 (2H); 1.77-2.18 (4H); 2.18-2.45 (2H); 3.14-3.32 (2H); 3.42-3.63 (2H); 3.63-3.84 (2H); 4.37 (0.1H); 4.48 (0.9H); 6.81-8.81 (4H).

LC / MS (ESI): 396.5; (calculated ([M + H] ⁺ ): 396.4).

Example AA2: AA2 molecule

Molecule A3: 15-methylhexadecan-1-ol.

In a three-necked flask under argon is introduced magnesium (9.46 g, 389 mmol) in shavings. The magnesium is covered with anhydrous THF (40 mL) and a few drops of l-bromo-3-methylbutane are added at room temperature to initiate the reaction. After observing an exotherm and a slight clouding of the medium, the rest of the 1-bromo-3-methylbutane (53.87 g, 357 mmol) is added dropwise over 90 min while the temperature of the medium remains stable between 50 and 60 ° C. The reaction medium is then heated at 70 ° C for 2 h.

In a three-necked flask under argon, to a CuCl solution (482 mg, 4.86 mmol) dissolved in the NMP (62 mL) at 0 ° C. is added dropwise a solution of 12bromo-l-dodecanol ( 43 g, 162.1 mmol) in THF (60 mL). To this solution is then added dropwise the solution of the hot organomagnesium freshly prepared so as to maintain the temperature of the medium below 20 ° C. The mixture is then stirred at room temperature for 16 h. The medium is cooled to 0 ° C and the reaction is stopped by adding an aqueous solution of HCl IN to pH 1 and the medium is extracted with ethyl acetate. After washing the organic phase with a saturated NaCl solution and drying over NazSCH, the solution is filtered and concentrated in vacuo to give an oil. After purification by DCVC on silica gel (cyclohexane, ethyl acetate), an oil which crystallizes at room temperature is obtained.

Yield: 32.8 g (74%)

NMR ^X H (CDCl₃, ppm): 0.87 (6H); 1.14 (2H); 1.20-1.35 (22H); 1.50-1.55 (3H); 3.64 (2H).

A4 molecule: 15-methylhexadecanoic acid.

To a solution of molecule A3 (20.65 g, 80.5 mmol) and tetrabutylammonium bromide (14.02 g, 42.5 mmol) in a mixture of acetic acid / dichlorethane / water (124/400 / 320 mL) at room temperature is added in small portions of potassium permanganate (38.2 g, 241.5 mmol). After stirring at reflux for 5 h and returning to room temperature, the medium is acidified to pH 1 by progressive addition of 5N HCl. Na2SC> 3 (44.6 g, 354.3 mmol) is then added gradually until the medium becomes discolored. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over Na2SC> 4, filtered and concentrated in vacuo. After purification by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid), a white solid is obtained.

Yield: 19.1 g (quantitative)

1 H NMR (CDCh, ppm): 0.87 (6H); 1.14 (2H); 1.22-1.38 (20H); 1.51 (1H); 1.63 (2H); 2.35 (2H).

A5_j molecule. product obtained by reaction between the molecule A4 and L-proline.

To a solution of molecule A4 (10 g, 37 mmol) in THF (360 mL) at 0 ° C are successively added dicyclohexyl carbodiimide (DCC) (8.01 g, 38.8 mmol) and N -hydroxysuccinimide (NHS) (4.47 g, 38.8 mmol). After 17 h of stirring at room temperature, the medium is cooled to 0 ° C for 20 min, filtered through a frit. L-proline (4 g, 37.7 mmol), triethylamine (34 mL) and water (30 mL) are added to the filtrate. After 20 h of stirring at room temperature, the medium is treated with an aqueous solution of HCl IN to pH 1. The aqueous phase is extracted with dichloromethane (2 x 125 mL). The combined organic phases are washed with an aqueous solution of IN HCl (2 x 100 mL), water (100 mL), then an aqueous solution saturated with NaCl (100 mL). After drying over Na2SO4, the organic phase is filtered, concentrated under vacuum and the residue is purified by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid)

Yield: 9.2 g (72%)

1 H NMR (CDCh, ppm): 0.86 (6H); 1.14 (2H); 1.22-1.38 (20H); 1.50 (1H); 1.67 (2H); 1.95-2.10 (3H); 2.34 (2H); 2.49 (1H); 3.47 (1H); 3.55 (1H); 4.61 (1H). LC / MS (ESI): 368.3; (calculated ([M + H] ⁺ ): 368.6).

A6 molecule: product obtained by reaction between the A5 molecule and Bocethylenediamine.

To a solution of molecule A5 (9.22 g, 25.08 mmol) in a THF / DMF mixture (200/50 mL) are added triethylamine (TEA) (5.23 mL) and 2- (1Henzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate (TBTU) at room temperature. After 10 min of stirring, Boc-ethylenediamine (4.42 g, 27.6 mmol) is added. After stirring at room temperature for 17 h, the mixture is diluted with water (300 mL) at 0 ° C and stirred cold for 20 min. The precipitate formed is filtered on a frit and the filtrate is extracted with ethyl acetate. The combined organic phases are washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, concentrated in vacuo and the residue is purified by flash chromatography (ethyl acetate, methanol).

Yield: 6.9 g (54%)

NMR ^X H (CDCl₃, ppm): 0.86 (6H); 1.15 (2H); 1.22-1.38 (20H); 1.43 (9H); 1.50 (1H); 1.64 (4H); 1.85 (1H); 1.95 (1H); 2.10 (1H); 2.31 (2H); 3.20-3.35 (3H); 3.45 (1H); 3.56 (1H); 4.51 (1H); 5.05 (1H); 7.24 (1H).

LC / MS (ESI): 510.6; (calculated ([M + H] ⁺ ): 510.8).

AA2 molecule [000385] To a solution of the molecule A6 (5.3 g, 10.40 mmol) in dichloromethane (50 mL) at 0 ° C is added a solution of 4N HCl in dioxane (13 mL). After 5 hours of stirring at 0 ° C., the medium is concentrated under vacuum, taken up in water and lyophilized to give a white solid of molecule AA2 in the form of the hydrochloride salt.

Yield: 4.6 g (99%)

^X H NMR (DZO, ppm): 0.91 (6H); 1.22 (2H); 1.22-1.50 (20H); 1.63 (3H); 1.98 (1H); 2.10 (2H); 2.26 (1H); 2.39 (1H); 2.43 (1H); 3.22 (2H); 3.45-3.60 (3H); 3.78 (1H); 4.42 (1H).

LC / MS (ESI): 410.4; (calculated ([M-CI] ⁺ ): 410.7).

Example AA3: AA3 molecule

Molecule A7: product obtained by the reaction between the molecule Al and Boctri (ethylene glycol) diamine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4.0 g, 11.3 mmol) and to Boc-tri (ethylene glycol) diamine (3.1 g, 12 , 4 mmol), a colorless oil is obtained after purification by flash chromatography (methanol, toluene).

Yield: 5.5 g (84%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.09-1.39 (24H); 1.44 (9H); 1.64 (2H); 1.79-2.01 (2H); 2.06-2.43 (4H); 3.23-3.68 (14H); 4.33 (0.2H); 4.56 (0.8H); 5.25 (1H); 6.49 (0.2H); 7.13-7.50 (0.8H).

AA3 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A7 molecule (5.5 g, 9.4 mmol), a white solid of molecule AA3 in the form of the hydrochloride salt is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 4.3 g (92%).

^X H NMR (DMSO-d6, ppm): 0.85 (3H); 1.08-1.40 (24H); 1.40-1.52 (2H); 1.71-2.02 (4H); 2.02-2.31 (2H); 2.90-2.98 (2H); 3.15-3.47 (5H); 3.50-3.66 (7H); 4.24 (0.6H); 4.32 (0.4H); 7.83 (0.6H); 7.95 (3H); 8.17 (0.4H).

LC / MS (ESI): 484.6; (calculated ([M + H] ⁺ ): 484.4).

Example AA4: AA4 molecule

Molecule A8: product obtained by the reaction between the molecule Al and Boc-1-amino4,7,10-trioxa-13-tridecane amine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4.5 g, 12.7 mmol) and to Boc-l-amino-4,7,10-trioxa- 13 tridecane amine (4.5 g, 14.0 mmol), a yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 7.7 g (92%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.22-1.37 (24H); 1.44 (9H); 1.59-1.67 (2H); 1.67-2.00 (6H); 2.06-2.45 (4H); 3.18-3.76 (18H); 4.28 (0.2H); 4.52 (0.8H); 4,695.04 (1H); 6.77 (0.2H); 7.20 (0.8H).

AA4 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A8 molecule (7.7 g, 11.8 mmol), a yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane ). Coevaporation with diisopropyl ether allows the molecule AA4 to be obtained in the form of the hydrochloride salt in the form of a white solid which is dried under vacuum at 50 ° C.

Yield: 5.4 g (76%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.08-1.40 (24H); 1.49-1.65 (2H); 1.76-2.39 (10H); 3.07-3.28 (3H); 3.34-3.80 (15H); 4.34 (0.05H); 4.64 (0.95H); 7.35 (0.05H); 7.66-8.58 (3.95H).

LC / MS (ESI): 556.7; (calculated ([M + H] ⁺ ): 556.5).

Example AA5: AA5 molecule [000390] A9 molecule; product obtained by reaction between the molecule Al and the methyl ester of N-Boc-L-lysine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4 g, 11.3 mmol) and to the methyl ester of N-Boc-Llysine (3.2 g, 12.4 mmol), a colorless oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 4.9 g (73%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 0.99-1.54 (37H); 1.54-1.75 (3H); 1.75-2.04 (3H); 2.04-2.41 (4H); 2.94-3.19 (2H); 3.19-3.81 (5H); 4.28-4.64 (2H); 4.94 (1H); 6.45 (0.1H); 7.36 (0.9H).

LC / MS (ESI): 596.7; (calculated ([M + H] ⁺ ): 596.5).

A10 molecule: product obtained by treatment of the A9 molecule with ammonia.

To a suspension of molecule A9 (4.9 g, 8.2 mmol) in 10 mL of methanol are added 320 mL of a solution of 7 N ammonia in methanol. After 19 h of stirring at room temperature in a closed atmosphere, an additional 100 ml of ammonia solution are added. After 24 h of stirring at room temperature in a closed atmosphere, the reaction medium is concentrated under reduced pressure. The residue is purified by trituration in diisopropyl ether at reflux (100 ml), to give a white solid which is dried under vacuum at 50 ° C.

Yield: 4.1 g (85%).

N ^N NMR (CDCh, ppm): 0.88 (3H); 1.06-1.57 (37H); 1.57-1.79 (3H); 1.88-2.41 (7H); 3.09 (2H); 3.49 (1H); 3.62 (1H); 4.34 (1H); 4.51 (1H); 4.69-4.81 (1H); 5.43 (0.95H); 5.57 (0.05H); 6.25 (0.05H); 6.52 (0.95H); 6.83 (0.05H); 7.11 (0.95H).

AA5 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A10 molecule (388 mg, 0.67 mmol), a white solid of AA5 molecule in the form of se! of hydrochloride is obtained after purification by trituration in diisopropyl ether.

Yield: 292 mg (85%).

¹ H NMR (DMSO-d6, ppm): 0.85 (3H); 1.06-2.34 (38H); 2.61-2.81 (2H); 3.29-3.68 (2H); 4.05-4.17 (1.7H); 4.42 (0.3H); 7.00 (1H); 7.16 (0.7H); 7.43 (0.3H); 7,738.04 (3.7H); 8.16 (0.3H).

LC / MS (ESI): 481.6; (calculated ([M + H] ⁺ ): 481.4).

Example AA6: AA6 molecule

Garlic molecule: product obtained by the reaction between stearoyl chloride and Lproline.

By a process similar to that used for the preparation of the molecule Al applied to L-proline (5.0 g, 43.4 mmol) and to stearoyl chloride (12.0 g, 39.6 mmol) , a white solid is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 5.37 g (36%)

NMR (CDCl3, ppm): 0.88 (3H); 1.26-1.37 (28H); 1.64-1.70 (2H); 1.88-2.10 (3H);

2.36 (2H); 2.54-2.58 (1H); 3.46 (1H); 3.56 (1H); 4.62 (1H).

LC / MS (ESI): 382.6; (calculated ([M + H] ⁺ ): 382.3).

Al2 molecule: product obtained by reaction between the Ail molecule and Boctri (ethylene glycol) diamine.

By a process similar to that used for the preparation of the molecule A6 applied to the molecule Ail (33.81 g, 88.6 mmol) and to Boc tri (ethylene glycol) diamine (26.4 g, 106, 3 mmol) in THF using DIPEA instead of TEA, a white solid is obtained after purification by flash chromatography (ethyl acetate, methanol).

Yield: 43.3 g (80%)

^X H NMR (CDCl, ppm): 0.87 (3H); 1.24 (30H); 1.43 (9H); 1.61 (2H); 1.82 (1H); 1.96 (1H); 2.25-2.45 (2H); 3.25-3.65 (14H); 4.30 (0.15H); 4.53 (0.85H); 5.25 (1H); 6.43 (0.15H); 7.25 (0.85H).

LC / MS (ESI): 612.6; (calculated ([M + H] ⁺ ): 612.9).

AA6 molecule By a process similar to that used for the preparation of the AA2 molecule applied to the A12 molecule (43 g, 70.3 mmol), the residue obtained after concentration under vacuum is triturated in acetonitrile. The suspension is filtered and the solid washed with acetonitrile and then acetone. After drying under vacuum, a white solid of molecule AA6 in the form of the hydrochloride salt is obtained.

Yield: 31.2 g (81%)

^X NMR (DMSO-de, ppm): 0.85 (3H); 1.23 (28H); 1.45 (2H); 1.70-2.05 (4H); 2.13 (1H); 2.24 (1H); 2.95 (2H); 3.10-3.25 (2H); 3.30-3.65 (10H); 4.20-4.45 (1H); 7.85-8.25 (4H).

LC / MS (ESI): 512.4; (calculated ([M-CI] ⁺ ): 512.8).

Example AA7: AA7 molecule

Molecule A13: product obtained by reaction between arachidic acid and ia L-proline. By a process similar to that used for the preparation of the molecule A5 applied to arachidic acid (15.51 g, 49.63 mmol) and to L-proline (6 g, 52.11 mmol) in using DIPEA instead of TEA, a white solid is obtained after purification by a chromatographic column on silica gei (cyclohexane, ethyl acetate, acetic acid).

Yield: 12.9 g (63%)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.28 (34H); 1.66 (2H); 1.95-2.15 (2H); 2.34 (2H); 2.45 (1H); 3.47 (1H); 3.56 (1H); 4.60 (1H).

LC / MS (ESI): 410.4; (calculated ([M + H] ⁺ ): 410.6).

A14 molecule: product obtained by the reaction between the A13 molecule and Boc-1-amino4,7,10-trioxa-13-tridecane.

By a process similar to that used for the preparation of the molecule A12 applied to the molecule A13 (10.96 g, 26.75 mmol) and to Boc-l-amino-4,7,10trioxa-13- tridecane (10.29 g, 32.11 mmol), a solid is obtained after purification by a chromatographic column on silica gel (cyclohexane, ethyl acetate, methanol).

Yield: 14.2 g (75%)

NMR (CDCb, ppm): 0.88 (3H); 1.24 (32H); 1.43 (9H); 1.61 (2H); 1.80 (1H); 1.96 (1H); 2.10-2.45 (4H); 3.20-3.75 (18H); 4.30 (0.20H); 4.55 (0.80H); 5.03 (1H); 6.75 (0.20H); 7.20 (0.80H).

LC / MS (ESI): 712.8; (calculated ([M + H] ⁺ ): 713.1).

AA7 molecule After a process similar to that used for the preparation of the AA2 molecule applied to the A14 molecule (14.25 g, 20.01 mmol), the residue obtained after concentration in vacuo of the reaction medium is dissolved in the methanol and evaporated under reduced pressure, the operation being repeated 4 times to give a white solid of molecule AA7 in the form of the hydrochloride salt.

Yield: 12.7 g (98%)

^X NMR (DMSO-de, ppm): 0.85 (3H); 1.23 (32H); 1.45 (2H); 1.64 (2H); 1.70-2.05 (6H); 2.10-2.30 (2H); 2.82 (2H); 3.08 (2H); 3.30-3.60 (15H); 4.15-4.30 (1H); 7.73-8.13 (4H).

LC / MS (ESI): 612.7; (calculated ([M-CI] ⁺ ): 612.9).

Example AA8: AAS molecule

A15 molecule; product obtained by the reaction between L-leucine and palmitoyl chloride.

By a process similar to that used for the preparation of the molecule Al applied to L-leucine (15.0 g, 114.4 mmol) and to palmitoyl chloride (34.5 g, 125 mmol), a white solid is obtained by trituration in diisopropyl ether. Yield: 13.0 g (31%)

NMR (CDCh, ppm): 0.88 (3H); 0.96 (6H); 1.16-1.35 (24H); 1.55-1.77 (5H); 2.23 (2H); 4.55-4.60 (1H); 5.88 (1H).

A16 molecule: product obtained by the reaction between the A15 molecule and the methyl ester of L-proline [000401] By a process similar to that used for the preparation of the A2 molecule applied to the A15 molecule (6.00 g, 16.2 mmol) and with the methyl ester of Lproline (3.23 g, 19.5 mmol), a slightly yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 5.8 g (74%)

^X H NMR (CDCIa, ppm): 0.83 to 1.00 (9H); 1.18-1.32 (24H); 1.40-1.73 (5H); 1.84-2.33 (6H); 3.47-3.89 (2H); 3.70 (1.14H); 3.71 (1.21H); 3.74 (0.53H); 3.76 (0.12H);

4.40-4.56 (1H); 4.63-4.67 (0.04H); 4.84 (0.38); 4.90 (0.40); 5.06 (0.18); 5.99 (0.18H); 6.08-6.21 (0.82).

LC / MS (ESI): 481.6; (calculated ([M + H] ⁺ ): 481.4).

A17 molecule: product obtained by the saponification of the methyl ester of the A16 molecule.

To a solution of molecule A16 (5.8 g, 12.06 mmol) in 30 mL of methanol is added 1N sodium hydroxide (13.5 mL, 13.5 mmol). After 20 h of stirring at room temperature, the solution is diluted with water and then acidified with 20 ml of 1N hydrochloric acid at 0 ° C. The precipitate is filtered and then rinsed with water (50 ml) before being dissolved in 50 ml of dichloromethane. The organic phase is dried over Na2SO4, filtered and then concentrated under reduced pressure to give a colorless oil. Yield: 4.5 g (80%)

NMR * Η (CDCIs, ppm): 0.85-0.99 (9H); 1.14-1.41 (24H); 1.43-1.72 (5H); 1.87-2.47 (7H); 3.48-3.55 (0.6H); 3.56-3.62 (0.4H); 3.83-3.90 (0.4H); 3.90-3.96 (0.6H); 4.52-4.56 (0.6H); 4.56-4.59 (0.4H); 4.80-4.86 (0.4H); 4.86-4.91 (0.6H); 6.05 (0.4H); 6.11 (0.6H).

LC / MS (EST): 467.6; (calculated ([M + H] ⁺ ): 467.4).

A18_2 molecule product obtained by the reaction between Boc-ethylenediamine and the A17 molecule.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule A17 (4.5 g, 9.64 mmol) and to Boc-ethylenediamine (1.70 g, 10.61 mmol) , a colorless oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 2.0 g (34%)

Ή NMR (CDCh, ppm): 0.83-0.99 (9H); 1.19-1.32 (24H); 1.44 (9H); 1.48-2.37 (14H); 3.09-3.99 (4H); 4.28-5.01 (2H); 5.64-6.04 (1H); 6.87-7.06 (1H).

LC / MS (ESI): 609.7; (calculated ([M + H] ⁺ ]: 609.5).

AA8 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A18 molecule (2 g, 3.28 mmol), a solid of molecule AA8 in the form of the hydrochloride salt is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 1.5 g (90%)

1 H NMR (CDCh, ppm): 0.83-1.00 (9H); 1.18-1.32 (24H); 1.37-1.77 (5H); 1.93-2.41 (6H); 3.07-3.97 (6H); 4.44-4.77 (2H); 7.66-8.21 (2H).

LC / MS (ESI): 509.6; (calculated ([M + H] ⁺ ): 509.4).

Example AA9: AA9 molecule

Molecule A19: product obtained by the reaction between lauric acid and L-phenylalanine. By a process similar to that used for the preparation of the molecule A5 applied to lauric acid (8.10 g, 40.45 mmol) and to L-phenylainanine (7 g, 42.38 mmol), a white solid is obtained.

Yield: 12.7 g (98%)

NMR (DMSO-de, ppm): 0.86 (3H); 1.10-1.30 (16H); 1.36 (2H); 2.02 (2H); 2.82 (1H); 3.05 (1H); 4.42 (1H); 7.15-7.30 (5H); 8.05 (1H); 12.61 (1H).

LC / MS (ESI): 348.2; (calculated ([M + H] ⁺ ): 348.5).

A20 molecule: product obtained by the reaction between the A19 molecule and the hydrochloride salt of the methyl ester of L-proline.

By a process similar to that used for the preparation of the molecule A6 applied to the molecule A19 (9.98 g, 28.72 mmol) and to the hydrochloride salt of the methyl ester of L-proine (5, 23 g, 31.59 mmol), a colorless oil is obtained after purification by a chromatographic column on silica gel (cyclohexane, ethyl acetate).

Yield: 5.75 g (44%)

1 H NMR (CDCh, ppm): 0.88 (3H); 1.10-1.30 (16H); 1.50-1.75 (3H); 1.80-2.02 (3H); 2.17 (2H); 2.65 (0.5H); 2.95 (1H); 3.05-3.20 (1.5H); 3.50-3.65 (1H); 3.75 (3H); 4.29 (0.5H)} 4.46 (0.5H); 4.70 (0.1H); 4.95 (0.9H); 6.20-6.30 (1H); 7.15-7.30 (5H).

LC / MS (ESI): 459.2; (calculated ([M + H] ⁺ ): 459.6).

A21 molecule: product obtained by saponification of the A20 molecule.

Lithium hydroxide (LiOH) is added to a solution of molecule A20 (5.75 g, 12.54 mmol) in a THF / methanol / water mixture (40/40/40 ml) at 0 ° C ) (600.49 mg, 25.07 mmol) then the mixture is stirred at room temperature for 20 h. After evaporation of the organic solvents under vacuum, the aqueous phase is diluted in water, acidified with an aqueous solution of IN HCl to pH 1. The product is then extracted with ethyl acetate. The combined organic phases are washed with a saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil.

Yield: 5.7 g (quantitative)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.10-1.30 (16H); 1.50-1.80 (3H); 1.67-2.02 (2H); 2.20 (2H); 2.25 (0.4H); 2.60 (0.6H); 2.85-3.10 (2.6H); 3.55-3.65 (1.4H); ; 4.35 (0.6H); 4.55 (0.4H); 4.94 (1H); 6.28 (0.4H); 6.38 (0.6H); 7.20-7.30 (5H).

LC / MS (ESI): 445.2; (calculated ([M + H] ⁺ ): 445.6).

Molecule A22: product obtained by reaction between Boc-ethylenediamine and the molecule A21.

By a process similar to that used for the preparation of the A6 molecule applied to the A21 molecule (5.67 g, 12.75 mmol) and to Boc-ethylenediamine (2.25 g, 14.03 mmol) , a colorless oil is obtained after purification by a chromatographic column on silica gel (dichloromethane, methanol).

Yield: 5.7 g (76%)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.25 (16H); 1.43 (9H); 1.58 (2.6H); 1.75-1.95 (1.4H); 2.15-2.30 (3H); 2.64 (0.5H); 2.95-3.10 (2.5H); 3.20-3.40 (4H); 3.45 (0.5H); 3.55 (0.2H); 3.66 (1H); 4.44 (1H); 4.50 (0.2H); 4.60 (0.6H); 4.99 (0.7H); 5.54 (0.5H); 5.95 (0.2H); 6.17 (1H); 6.60 (0.5H); 7.07 (0.5H); 7.20-7.40 (5H). LC / MS (ESI): 587.4; (calculated ([M + H] ⁺ ): 587.8).

AA9 molecule After a process similar to that used for the preparation of the AA2 molecule applied to the A22 molecule (5.66 g, 9.65 mmol), the residue obtained after vacuum concentration of the reaction medium is dissolved in the methanol and evaporated under reduced pressure, the operation being repeated 4 times to give a white foam of molecule AA9 in the form of the hydrochloride salt.

Yield: 4.9 g (97%)

^X NMR (DMSO-de, 120 ° C, ppm): 0.89 (3H); 1.26 (16H); 1.43 (2H); 1.68 (0.6H); 1.75-2.00 (3H); 2.05-2.25 (2.4H); 2.82-3.05 (5H); 3.38 (2H); 3.50-3.70 (1.4H); 4.25 (0.6H); 4.63 (0.4H); 4.77 (0.6H); 7.25-7.50 (5H); 7.55-8.20 (4H).

LC / MS (EST): 487.4; (calculated ([M-CI] ⁺ ): 487.7).

Example AAI: AAI molecule

Molecule Al: Product obtained by the reaction between palmitoyl chloride and Lproline.

To a solution of L-proline (10.6 g, 92.1 mmol) in 1 N aqueous sodium hydroxide (230 mL; 230 mmol) is added dropwise for 90 min a solution of palmitoyl chloride ( 23.0 g, 83.7 mmol) in acetone (167 mL). After 14 h of stirring at room temperature, the heterogeneous mixture is cooled to 0 ° C., then filtered through a frit to give a white solid which is washed with water (2 x 100 mL) then diisopropyl ether (100 mL) . The solid is dried under reduced pressure. The solid is then dissolved at reflux in 200 ml of water and then 8 ml of a hydrochloric acid solution at 37% are added to obtain a pH = 1. The opalescent reaction medium is then cooled to 0 ° C. The precipitate obtained is filtered on a frit and then washed with water (5 x 50 mL) until filtrates of physiological pH between 6.0 and 8.0 are obtained, then they are dried in an oven at 50 ° C under empty overnight. The product is purified by recrystallization from diisopropyl ether. A white solid is obtained.

Yield: 22.7 g (77%).

1 H NMR (CDCh, ppm): 0.88 (3H); 1.19-1.45 (24H); 1.58-1.74 (2H); 1.88-2.14 (3H); 2.15-2.54 (3H); 3.47 (1H); 3.58 (1H); 4.41 (0.1H); 4.61 (0.9H) 6.60-8.60 (1H).

Molecule A2: Product obtained by reaction between the molecule Al and Bocethylenediamine.

To a solution of molecule Al (75.1 g, 212.4 mmol) in 1500 ml of chloroform are added successively and at room temperature N, Ndiisopropylethylamine (DIPEA) (68.8 g, 532.3 mmol ), 1-hydroxybenzotriazole (HOBt) (37.1 g, 274.6 mmol) then / V- (3-dimethylaminopropyl) - / V'-ethylcarbodiimide (EDC) (53.1 g, 277.0 mmol) . After 15 min of stirring at room temperature, a solution of Boc-ethylenediamine (BocEDA) (37.6 g, 234.7 mmol) in 35 ml of chloroform is added. After 18 h of stirring at room temperature, a 0.1 N HCl solution (2.1 L), then a saturated NaCl solution (1 L) are added. The phases are separated then the organic phase is washed successively with a 0.1 N HCl solution / saturated NaCl (2.1 L / l L), a saturated NaCl solution (2 L), a saturated NaHCO3 solution (2 L), then a saturated NaCl solution (2 L). The organic phase is dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained is purified by trituration in diisopropyl ether (3 x 400 mL), to give a solid after drying under vacuum at 40 ° C.

Yield: 90.4 g (86%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.20-1.37 (24H); 1.44 (9H); 1.54-1.70 (2H); 1.79-1.92 (1H); 1.92-2.04 (1H); 2.03-2.17 (1H); 2.17-2.44 (3H); 3.14-3.36 (4H); 3.43 (1H); 3.56 (1H); 4.29 (0.1 H); 4.51 (0.9 H); 4.82 (0.1H); 5.02 (0.9H); 6.84 (0.1H); 7.22 (0.9H).

AAI molecule [000413] To a solution of molecule A2 (20.1 g, 40.5 mmol) in 330 mL of dichloromethane is added dropwise and at 0 ° C a solution of 4N hydrochloric acid in dioxane (100 mL, 400 mmol). After 3 h 30 min of stirring at room temperature, the solution is concentrated under reduced pressure. The residue is purified by flash chromatography (methanol, dichloromethane) to give a white solid of molecule AAI in the form of the hydrochloride salt.

Yield: 16.3 g (93%).

NMR (CDCh, ppm): 0.88 (3H); 1.07-1.40 (24H); 1.49-1.63 (2H); 1.77-2.18 (4H); 2.18-2.45 (2H); 3.14-3.32 (2H); 3.42-3.63 (2H); 3.63-3.84 (2H); 4.37 (0.1H); 4.48 (0.9H); 6.81-8.81 (4H).

LC / MS (ESI): 396.5; (calculated ([M + H] ⁺ ): 396.4).

Example AA2: AA2 molecule

Molecule A3: 15-methylhexadecan-1-ol.

[000414] Magnesium (9.46 g, 389 mmol) in chips is introduced into a three-necked flask under argon. The magnesium is covered with anhydrous THF (40 mL) and a few drops of l-bromo-3-methylbutane are added at room temperature to initiate the reaction. After observing an exotherm and a slight clouding of the medium, the rest of the 1-bromo-3-methylbutane (53.87 g, 357 mmol) is added dropwise over 90 min while the temperature of the medium remains stable between 50 and 60 ° C. The reaction medium is then heated at 70 ° C for 2 h.

In a three-necked flask under argon, to a CuCl solution (482 mg, 4.86 mmol) dissolved in the NMP (62 mL) at 0 ° C. is added dropwise a solution of 12bromo-l-dodecanol ( 43 g, 162.1 mmol) in THF (60 mL). To this solution is then added dropwise the solution of the hot organomagnesium freshly prepared so as to maintain the temperature of the medium below 20 ° C. The mixture is then stirred at room temperature for 16 h. The medium is cooled to 0 ° C. and the reaction is stopped by adding an aqueous 1N HCl solution to pH 1 and the medium is extracted with ethyl acetate. After washing the organic phase with a saturated NaCl solution and drying over NazSCh, the solution is filtered and concentrated in vacuo to give an oil. After purification by DCVC on silica gel (cyclohexane, ethyl acetate), an oil which crystallizes at room temperature is obtained.

Yield: 32.8 g (74%)

NMR ^X H (CDCl₃, ppm): 0.87 (6H); 1.14 (2H); 1.20-1.35 (22H); 1.50-1.55 (3H); 3.64 (2H).

A4 molecule: 15-methylhexadecanoic acid.

To a solution of molecule A3 (20.65 g, 80.5 mmol) and tetrabutylammonium bromide (14.02 g, 42.5 mmol) in a mixture of acetic acid / dichlorethane / water (124/400 / 320 mL) at room temperature is added in small portions of potassium permanganate (38.2 g, 241.5 mmol). After stirring at reflux for 5 h and returning to ambient temperature, the medium is acidified to pH 1 by gradual addition of 5N HCl. Na2SO3 (44.6 g, 354.3 mmol) is then added gradually until the medium discolours . The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over Na2SC> 4, filtered and concentrated in vacuo. After purification by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid), a white solid is obtained.

Yield: 19.1 g (quantitative)

^X NMR (CDCl3, ppm): 0.87 (6H); 1.14 (2H); 1.22-1.38 (20H); 1.51 (1H); 1.63 (2H); 2.35 (2H).

A5 molecule; Product obtained by reaction between the molecule A4 and L-proline.

To a solution of molecule A4 (10 g, 37 mmol) in THF (360 mL) at 0 ° C are successively added dicyclohexyl carbodiimide (DCC) (8.01 g, 38.8 mmol) and / V-hydroxysuccinimide (NHS) (4.47 g, 38.8 mmol). After 17 h of stirring at room temperature, the medium is cooled to 0 ° C for 20 min, filtered through a frit. L-proline (4 g, 37.7 mmol), triethylamine (34 mL) and water (30 mL) are added to the filtrate. After 20 h of stirring at room temperature, the medium is treated with a 1N aqueous HCl solution to pH 1. The aqueous phase is extracted with dichloromethane (2 x 125 mL). The combined organic phases are washed with a 1N aqueous HCl solution (2 x 100 mL), water (100 mL), then an aqueous solution saturated with NaCl (100 mL). After drying over Na2SO4, the organic phase is filtered, concentrated under vacuum and the residue is purified by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid)

Yield: 9.2 g (72%)

NMR ^X H (CDCl₃, ppm): 0.86 (6H); 1.14 (2H); 1.22-1.38 (20H); 1.50 (1H); 1.67 (2H); 1.95-2.10 (3H); 2.34 (2H); 2.49 (1H); 3.47 (1H); 3.56 (1H); 4.61 (1H).

LC / MS (ESI): 368.3; (calculated ([M + H] ⁺ ]: 368.6).

A6 molecule: Product obtained by reaction between the A5 molecule and Bocethylenediamine.

To a solution of molecule A5 (9.22 g, 25.08 mmol) in a THF / DMF mixture (200/50 mL) are added triethylamine (TEA) (5.23 mL) and 2- (1Henzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate (TBTU) at room temperature. After 10 min of stirring, Boc-ethylenediamine (4.42 g, 27.6 mmol) is added. After stirring at room temperature for 17 h, the mixture is diluted with water (300 mL) at 0 ° C and stirred cold for 20 min. The precipitate formed is filtered on a frit and the filtrate is extracted with ethyl acetate. The combined organic phases are washed with saturated NaHCCh solution, dried over NazSCU, filtered, concentrated in vacuo and the residue is purified by flash chromatography (ethyl acetate, methanol).

Yield: 6.9 g (54%)

NMR ^X H (CDCl₃, ppm): 0.86 (6H); 1.15 (2H); 1.22-1.38 (20H); 1.43 (9H); 1.50 (1H); 1.64 (4H); 1.85 (1H); 1.95 (1H); 2.10 (1H); 2.31 (2H); 3.20-3.35 (3H); 3.45 (1H); 3.56 (1H); 4.51 (1H); 5.05 (1H); 7.24 (1H).

LC / MS (ESI): 510.6; (calculated ([M + H] ⁺ ): 510.8).

AA2 molecule [000419] To a solution of the molecule A6 (5.3 g, 10.40 mmol) in dichloromethane (50 mL) at 0 ° C is added a solution of 4N HCl in dioxane (13 mL). After 5 hours of stirring at 0 ° C., the medium is concentrated under vacuum, taken up in water and lyophilized to give a white solid of molecule AA2 in the form of the hydrochloride salt.

Yield: 4.6 g (99%)

Ή NMR (DzO, ppm): 0.91 (6H); 1.22 (2H); 1.22-1.50 (20H); 1.63 (3H); 1.98 (1H); 2.10 (2H); 2.26 (1H); 2.39 (1H); 2.43 (1H); 3.22 (2H); 3.45-3.60 (3H); 3.78 (1H); 4.42 (1H).

LC / MS (ESI): 410.4; (calculated ([M + H] ⁺ ): 410.7).

Example AA3: AA3 molecule

Molecule A7: Product obtained by the reaction between the molecule Al and Boctri (ethylene glycol) diamine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4.0 g, 11.3 mmol) and to Boc-tri (ethylene glycol) diamine (3.1 g, 12 , 4 mmol), a colorless oil is obtained after purification by flash chromatography (methanol, toluene).

Yield: 5.5 g (84%).

NMR (CDCh, ppm): 0.88 (3H); 1.09-1.39 (24H); 1.44 (9H); 1.64 (2H); 1.79-2.01 (2H); 2.06-2.43 (4H); 3.23-3.68 (14H); 4.33 (0.2H); 4.56 (0.8H); 5.25 (1H); 6.49 (0.2H); 7.13-7.50 (0.8H).

AA3 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A7 molecule (5.5 g, 9.4 mmol), a white solid of molecule AA3 in the form of the hydrochloride salt is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 4.3 g (92%).

^X H NMR (DMSO-d6, ppm): 0.85 (3H); 1.08-1.40 (24H); 1.40-1.52 (2H); 1.71-2.02 (4H); 2.02-2.31 (2H); 2.90-2.98 (2H); 3.15-3.47 (5H); 3.50-3.66 (7H); 4.24 (0.6H); 4.32 (0.4H); 7.83 (0.6H); 7.95 (3H); 8.17 (0.4H).

LC / MS (ESI): 484.6; (calculated ([M + H] ⁺ ): 484.4).

Example AA4: AA4 molecule

Molecule A8: Product obtained by the reaction between the molecule Al and Boc-1-amino4,7,10-trioxa-13-tridecane amine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4.5 g, 12.7 mmol) and to Boc-l-amino-4,7,10-trioxa- 13 tridecane amine (4.5 g, 14.0 mmol), a yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 7.7 g (92%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.22-1.37 (24H); 1.44 (9H); 1.59-1.67 (2H); 1.67-2.00 (6H); 2.06-2.45 (4H); 3.18-3.76 (18H); 4.28 (0.2H); 4.52 (0.8H); 4,695.04 (1H); 6.77 (0.2H); 7.20 (0.8H).

AA4 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A8 molecule (7.7 g, 11.8 mmol), a yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane ). Coevaporation with diisopropyl ether allows the molecule AA4 to be obtained in the form of the hydrochloride salt in the form of a white solid which is dried under vacuum at 50 ° C.

Yield: 5.4 g (76%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.08-1.40 (24H); 1.49-1.65 (2H); 1.76-2.39 (10H); 3.07-3.28 (3H); 3.34-3.80 (15H); 4.34 (0.05H); 4.64 (0.95H); 7.35 (0.05H); 7.65-8.58 (3.95H).

LC / MS (ESI): 556.7; (calculated ([M + H] ⁺ ): 556.5).

Example AA5: AA5 molecule

Molecule A9: Product obtained by reaction between the molecule Al and the methyl ester of / V-Boc-L-lysine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4 g, 11.3 mmol) and to the methyl ester of / V-Boc-Llysine (3.2 g , 12.4 mmol), a colorless oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 4.9 g (73%).

N ^N NMR (CDCh, ppm): 0.88 (3H); 0.99-1.54 (37H); 1.54-1.75 (3H); 1.75-2.04 (3H); 2.04-2.41 (4H); 2.94-3.19 (2H); 3.19-3.81 (5H); 4.28-4.64 (2H); 4.94 (1H); 6.45 (0.1H); 7.36 (0.9H).

LC / MS (ESI): 596.7; (calculated ([M + H] ⁺ ): 596.5).

Molecule A10: Product obtained by treatment of the molecule A9 with ammonia. To a suspension of molecule A9 (4.9 g, 8.2 mmol) in 10 ml of methanol are added 320 ml of a solution of 7 N ammonia in methanol. After 19 h of stirring at room temperature in a closed atmosphere, an additional 100 ml of ammonia solution are added. After 24 h of stirring at room temperature in a closed atmosphere, the reaction medium is concentrated under reduced pressure. The residue is purified by trituration in diisopropyl ether at reflux (100 ml), to give a white solid which is dried under vacuum at 50 ° C.

Yield: 4.1 g (85%).

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.06-1.57 (37H); 1.57-1.79 (3H); 1.88-2.41 (7H); 3.09 (2H); 3.49 (1H); 3.62 (1H); 4.34 (1H); 4.51 (1H); 4.69-4.81 (1H); 5.43 (0.95H); 5.57 (0.05H); 6.25 (0.05H); 6.52 (0.95H); 6.83 (0.05H); 7.11 (0.95H).

AA5 molecule By a process similar to that used for the preparation of the molecule

AAI applied to the molecule A10 (388 mg, 0.67 mmol), a white solid of molecule AA5 in the form of the hydrochloride salt is obtained after purification by trituration in diisopropylether.

Yield: 292 mg (85%).

^X H NMR (DMSO-d6, ppm): 0.85 (3H); 1.06-2.34 (38H); 2.61-2.81 (2H); 3.29-3.68 (2H); 4.05-4.17 (1.7H); 4.42 (0.3H); 7.00 (1H); 7.16 (0.7H); 7.43 (0.3H); 7,738.04 (3.7H); 8.16 (0.3H).

LC / MS (ESI): 481.6; (calculated ([M + H] ⁺ ): 481.4).

Example AA6: AA6 molecule

Garlic Molecule: Product obtained by the reaction between stearoyl chloride and Lproline.

By a process similar to that used for the preparation of the molecule Al applied to L-proline (5.0 g, 43.4 mmol) and to stearoyl chloride (12.0 g, 39.6 mmol) , a white solid is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 5.37 g (36%)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.26-1.37 (28H); 1.64-1.70 (2H); 1.88-2.10 (3H); 2.36 (2H); 2.54-2.58 (1H); 3.46 (1H); 3.56 (1H); 4.62 (1H).

LC / MS (ESI): 382.6; (calculated ([M + H] ⁺ ): 382.3).

Molecule A12: Product obtained by reaction between the molecule Ail and Boctri (ethylene glycol) diamine.

By a process similar to that used for the preparation of the A6 molecule applied to the Ail molecule (33.81 g, 88.6 mmol) and to Boctri (ethylene glycol) diamine (26.4 g, 106.3 mmol) in THF using DIPEA instead of TEA, a white solid is obtained after purification by flash chromatography (ethyl acetate, methanol).

Yield: 43.3 g (80%)

NMR ^X H (CDCl₃, ppm): 0.87 (3H); 1.24 (30H); 1.43 (9H); 1.61 (2H); 1.82 (1H); 1.96 (1H); 2.25-2.45 (2H); 3.25-3.65 (14H); 4.30 (0.15H); 4.53 (0.85H); 5.25 (1H); 6.43 (0.15H); 7.25 (0.85H).

LC / MS (ESI): 612.6; (calculated ([M + H] ⁺ ): 612.9).

AA6 molecule By a process similar to that used for the preparation of the AA2 molecule applied to the A12 molecule (43 g, 70.3 mmol), the residue obtained after concentration under vacuum is triturated in acetonitrile. The suspension is filtered and the solid washed with acetonitrile and then acetone. After drying under vacuum, a white solid of molecule AA6 in the form of the hydrochloride salt is obtained.

Yield: 31.2 g (81%)

1 H NMR (DMSO-de, ppm): 0.85 (3H); 1.23 (28H); 1.45 (2H); 1.70-2.05 (4H); 2.13 (1H); 2.24 (1H); 2.95 (2H); 3.10-3.25 (2H); 3.30-3.65 (10H); 4.20-4.45 (1H); 7.85-8.25 (4H).

LC / MS (ESI): 512.4; (calculated ([M + H] ⁺ ): 512.8).

Example AA7: AA7 molecule

Molecule AI3: Product obtained by reaction between arachidic acid and L-proline. By a process similar to that used for the preparation of the molecule A5 applied to arachidic acid (15.51 g, 49.63 mmol) and to its L-proline (6 g, 52.11 mmol) in using DIPEA instead of TEA, a white solid is obtained after purification by a chromatographic column on silica gel (cyclohexane, ethyl acetate, acetic acid).

Yield: 12.9 g (63%)

NMR (CDCh, ppm): 0.88 (3H); 1.28 (34H); 1.66 (2H); 1.95-2.15 (2H); 2.34 (2H); 2.45 (1H); 3.47 (1H); 3.56 (1H); 4.60 (1H).

LC / MS (ESI): 410.4; (calculated ([M + H] ⁺ ): 410.6).

Molecule A14: Product obtained by the reaction between the molecule A13 and Boc-1-amino4,7,10-trioxa-13-tridecane.

By a process similar to that used for the preparation of the molecule

A12 applied to the molecule A13 (10.96 g, 26.75 mmol) and to Boc-1-amino-4,7,10trioxa-13-tridecane (10.29 g, 32.11 mmol), a solid is obtained after purification by chromatographic column on silica gel (cyclohexane, ethyl acetate, methanol).

Yield: 14.2 g (75%)

1 H NMR (CDCh, ppm): 0.88 (3H); 1.24 (32H); 1.43 (9H); 1.61 (2H); 1.80 (1H);

1.96 (1H); 2.10-2.45 (4H); 3.20-3.75 (18H); 4.30 (0.20H); 4.55 (0.80H); 5.03 (1H); 6.75 (0.20H); 7.20 (0.80H).

LC / MS (ESI): 712.8; (calculated ([M + H] ⁺ ): 713.1).

AA7 molecule After a process similar to that used for the preparation of the AA2 molecule applied to the A14 molecule (14.25 g, 20.01 mmol), the residue obtained after vacuum concentration of the reaction medium is dissolved in the methanol and evaporated under reduced pressure, the operation being repeated 4 times to give a white solid of molecule AA7 in the form of the hydrochloride salt.

Yield: 12.7 g (98%)

^X H NMR (DMSO-d, ppm): 0.85 (3H); 1.23 (32H); 1.45 (2H); 1.64 (2H); 1.70-2.05 (6H); 2.10-2.30 (2H); 2.82 (2H); 3.08 (2H); 3.30-3.60 (15H); 4.15-4.30 (1H); 7.73-8.13 (4H).

LC / MS (ESI): 612.7; (calculated ([M + H] ⁺ ): 612.9).

Example AA8: AAS molecule

Molecule AI5: Product obtained by the reaction between L-leucine and palmitoyl chloride.

By a process similar to that used for the preparation of the molecule Al applied to L-leucine (15.0 g, 114.4 mmol) and to palmitoyl chloride (34.5 g, 125 mmol), a white solid is obtained by trituration in diisopropyl ether.

Yield: 13.0 g (31%)

1 H NMR (CDCh, ppm): 0.88 (3H); 0.96 (6H); 1.16-1.35 (24H); 1.55-1.77 (5H); 2.23 (2H); 4.55-4.60 (1H); 5.88 (1H).

A16 molecule: Product obtained by the reaction between the A15 molecule and the methyl ester of L-proline [000434] By a process similar to that used for the preparation of the A2 molecule applied to the A15 molecule (6.00 g, 16.2 mmol) and with the methyl ester of Lproline (3.23 g, 19.5 mmol), a slightly yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 5.8 g (74%)

^X H NMR (CDCIa, ppm): 0.83 to 1.00 (9H); 1.18-1.32 (24H); 1.40-1.73 (5H); 1.84-2.33 (6H); 3.47-3.89 (2H); 3.70 (1.14H); 3.71 (1.211-1); 3.74 (0.53H); 3.76 (0.12H); 4.40-4.56 (1H); 4.63-4.67 (0.04H); 4.84 (0.38); 4.90 (0.40); 5.06 (0.18); 5.99 (0.18H); 6.08-6.21 (0.82).

LC / MS (ESI): 481.6; (calculated ([M + H] ⁺ ): 481.4).

Molecule A17: Product obtained by the saponification of the methyl ester of the molecule A16.

To a solution of molecule A16 (5.8 g, 12.06 mmol) in 30 mL of methanol is added 1N sodium hydroxide (13.5 mL, 13.5 mmol). After 20 h of stirring at room temperature, the solution is diluted with water and then acidified with 20 ml of 1N hydrochloric acid at 0 ° C. The precipitate is filtered and then rinsed with water (50 ml) before being dissolved in 50 ml of dichloromethane. The organic phase is dried over Na2SO4, filtered and then concentrated under reduced pressure to give a colorless oil.

Yield: 4.5 g (80%)

^X NMR (CDCl3, ppm): 0.85 to 0.99 (9H); 1.14-1.41 (24H); 1.43-1.72 (5H); 1.87-2.47 (7H); 3.48-3.55 (0.6H); 3.56-3.62 (0.4H); 3.83-3.90 (0.4H); 3.90-3.96 (0.6H); 4.52-4.56 (0.6H); 4.56-4.59 (0.4H); 4.80-4.86 (0.4H); 4.86-4.91 (0.6H); 6.05 (0.4H); 6.11 (0.6H).

LC / MS (ESI): 467.6; (calculated ([M + H] ⁺ ): 467.4).

A18 molecule: Product obtained by the reaction between Boc-ethylenediamine and the A17 molecule.

By a process similar to that used for the preparation of the molecule

A2 applied to the molecule A17 (4.5 g, 9.64 mmol) and to Boc-ethylenediamine (1.70 g,

10.61 mmol), a colorless oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 2.0 g (34%)

¹ H NMR (CDCh, ppm): 0.83-0.99 (9H); 1.19-1.32 (24H); 1.44 (9H); 1.48-2.37 (14H); 3.09-3.99 (4H); 4.28-5.01 (2H); 5.64-6.04 (1H); 6.87-7.06 (1H).

LC / MS (ESI): 609.7; (calculated ([M + H] ⁺ ): 609.5).

AA8 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A18 molecule (2 g, 3.28 mmol), a solid of molecule AA8 in the form of the hydrochloride salt is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 1.5 g (90%)

NMR ^X H (CDCl₃, ppm): 0.83 to 1.00 (9H); 1.18-1.32 (24H); 1.37-1.77 (5H) 1.93-2.41 (6H); 3.07-3.97 (6H); 4.44-4.77 (2H); 7.66-8.21 (2H).

LC / MS (ESI): 509.6; (calculated ([M + H] ⁺ ): 509.4).

Example AA9: AA9 molecule

Molecule Al9: Product obtained by the reaction between isauric acid and L-phenylalanine.

By a process similar to that used for the preparation of the molecule A5 applied to Iauric acid (8.10 g, 40.45 mmol) and to L-phenylalanine (7 g, 42.38 mmol), a white solid is obtained.

Yield: 12.7 g (98%)

^X NMR (DMSO-de, ppm): 0.86 (3H); 1.10-1.30 (16H); 1.36 (2H); 2.02 (2H); 2.82 (1H); 3.05 (1H); 4.42 (1H); 7.15-7.30 (5H); 8.05 (1H); 12.61 (1H).

LC / MS (ESI): 348.2; (calculated ([M + H] ⁺ ): 348.5).

Molecule A20: Product obtained by the reaction between the molecule A19 and the hydrochloride salt of the methyl ester of L-proline.

By a process similar to that used for the preparation of the molecule A6 applied to the molecule A19 (9.98 g, 28.72 mmol) and to the hydrochloride salt of the methyl ester of L-proline (5, 23 g, 31.59 mmol), a colorless oil is obtained after purification by a chromatographic column on silica gel (cyclohexane, ethyl acetate).

Yield: 5.75 g (44%)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.10-1.30 (16H); 1.50-1.75 (3H); 1.80-2.02 (3H); 2.17 (2H); 2.65 (0.5H); 2.95 (1H); 3.05-3.20 (1.5H); 3.50-3.65 (1H); 3.75 (3H); 4.29 (0.5H); 4.46 (0.5H); 4.70 (0.1H); 4.95 (0.9H); 6.20-6.30 (1H); 7.15-7.30 (5H).

LC / MS (ESI): 459.2; (calculated ([M + H] ⁺ ): 459.6).

A21 molecule: Product obtained by saponification of the A20 molecule.

Lithium hydroxide (LiOH) is added to a solution of molecule A20 (5.75 g, 12.54 mmol) in a THF / methanol / water mixture (40/40/40 mL) at 0 ° C ) (600.49 mg, 25.07 mmol) then the mixture is stirred at room temperature for 20 h. After evaporation of the organic solvents under vacuum, the aqueous phase is diluted in water, acidified with a 1N aqueous HCl solution to pH 1. The product is then extracted with ethyl acetate. The combined organic phases are washed with a saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil.

Yield: 5.7 g (quantitative)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.10-1.30 (16H); 1.50-1.80 (3H); 1.67-2.02 (2H); 2.20 (2H); 2.25 (0.4H); 2.60 (0.6H); 2.85-3.10 (2.6H); 3.55-3.65 (1.4H); ; 4.35 (0.6H); 4.55 (0.4H); 4.94 (1H); 6.28 (0.4H); 6.38 (0.6H); 7.20-7.30 (5H).

LC / MS (ESI): 445.2; (calculated ([M + H] ⁺ ): 445.6).

Molecule A22: Product obtained by reaction between Boc-ethylenediamine and the molecule A21.

By a process similar to that used for the preparation of the molecule

A6 applied to the molecule A21 (5.67 g, 12.75 mmol) and to Boc-ethylenediamine (2.25 g, 14.03 mmol), a colorless oil is obtained after purification by chromatographic column on silica gel ( dichloromethane, methanol).

Yield: 5.7 g (76%)

1 H NMR (CDCh, ppm): 0.88 (3H); 1.25 (16H); 1.43 (9H); 1.58 (2.6H); 1.75-1.95 (1.4H); 2.15-2.30 (3H); 2.64 (0.5H); 2.95-3.10 (2.5H); 3.20-3.40 (4H); 3.45 (0.5H); 3.55 (0.2H); 3.66 (1H); 4.44 (1H); 4.50 (0.2H); 4.60 (0.6H); 4.99 (0.7H); 5.54 (0.5H); 5.95 (0.2H); 6.17 (1H); 6.60 (0.5H); 7.07 (0.5H); 7.20-7.40 (5H).

LC / MS (ESI): 587.4; (calculated ([M + H] ⁺ ): 587.8).

AA9 molecule After a process similar to that used for the preparation of the AA2 molecule applied to the A22 molecule (5.66 g, 9.65 mmol), the residue obtained after concentration under vacuum of the reaction medium is dissolved in the methanol and evaporated under reduced pressure, the operation being repeated 4 times to give a white foam of molecule AA9 in the form of the hydrochloride salt.

Yield: 4.9 g (97%)

^X NMR (DMSO-de, 120 ° C, ppm): 0.89 (3H); 1.26 (16H); 1.43 (2H); 1.68 (0.6H); 1.75-2.00 (3H); 2.05-2.25 (2.4H); 2.82-3.05 (5H); 3.38 (2H); 3.50-3.70 (1.4H); 4.25 (0.6H); 4.63 (0.4H); 4.77 (0.6H); 7.25-7.50 (5H); 7.55-8.20 (4H).

LC / MS (ESI): 487.4; (calculated ([M + H] ⁺ ): 487.7).

Example AA10: AA10 molecule

Molecule A23: Product obtained by the reaction between molecule B7 and Bocethylenediamine [000444] To a solution of molecule B7 (190.00 g, 583.73 mmol) at 0 ° C in DCM (2.9 L) are added successively HOBt (8.94 g, 58.37 mmol) then Bocethylenediamine (112.20 g, 700.00 mmol) dissolved in DCM (150 mL). EDC (123.10 g, 642.00 mmol) is added and then the mixture is stirred for 17 h between 0 ° C and room temperature. The reaction mixture is then washed with an aqueous solution, a saturated aqueous solution of NaHCU3 (2x1.5 L), an aqueous solution of 1 N HCl (2x1.5 L) and then a saturated aqueous solution of NaCl (1.5 L), dried over Na2SÜ4, filtered and concentrated under reduced pressure. A white solid is obtained after recrystallization from acetonitrile.

Yield: 256.50 g (93%)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.16-1.38 (20H); 1.44 (9H); 1.56-1.71 (2H); 1.78-2.45 (6H); 3.11-3.72 (6H); 4.30 (O, 1H); 4.51 (0.9H); 4.87 (O, 1H); 5.04 (0.9H); 6.87 (O, 1H); 7.23 (0.9H).

LC / MS (ESI): 468.0; (calculated ([M + H] ⁺ ): 468.4).

AA10 molecule After a process similar to that used for the preparation of the AAI molecule applied to the A23 molecule (256.50 g, 548.43 mmol), a white solid of molecule AA10 in the form of the hydrochloride salt is obtained by trituration in pentane (1.6 L) and drying under reduced pressure at 40 ° C.

Yield: 220.00 g (99%)

^X H NMR (MeOD-d4, ppm): 0.90 (3H); 1.21-1.43 (20H); 1.54-1.66 (2H); 1.85-2.28 (4H); 2.39 (2H); 3.00-3.17 (2H); 3.30-3.40 (1H); 3.43-3.71 (3H); 4.29 (0.94H);

4.48 (0.06H).

LC / MS (ESI): 368.2; (calculated ([M + H] ⁺ ): 368.3).

Example AA11: AA11 molecule

Molecule A24: Product obtained by the reaction between molecule B7 and Boc-1-amino4,7,10-trioxa-13-tridecane amine.

By a process similar to that used for the preparation of the molecule A23 applied to the molecule B7 (24.00 g, 73.73 mmol) and to Boc-l-amino-4,7,10-trioxa13-tridecane amine (28.35 g, 88.48 mmol), an orange oil of molecule A24 is obtained.

Yield: 44.50 g (96%)

1H NMR (CDCh, ppm): 0.87 (3H); 1.08-1.56 (20H); 1.43 (9H); 1.58-1.67 (2H); 1.70-2.00 (6H); 2.04-2.41 (4H); 3.16-3.77 (18H); 4.26-4.29 (0.2H); 4.50-4.54 (0.8H); 4.68-5.10 (1H); 6.74 (0.2H); 7.19 (0.8H).

LC / MS (ESI): 628.4; (calculated ([M + H] ⁺ ): 628.5).

AA11 molecule After a process similar to that used for the preparation of the AAI molecule applied to the A24 molecule (43.40 g, 69.12 mmol), a white solid of molecule AA11 in the form of the hydrochloride salt is obtained after trituration 3 times in diethyl ether, solubilization of the residue in water and lyophilization.

Yield: 38.70 g (98%)

1H NMR (DMSO, ppm): 0.85 (3H); 1.07-1.38 (20H); 1.41-1.52 (2H); 1.55-1.66 (2H); 1.70-2.02 (6H); 2.08-2.30 (2H); 2.78-2.87 (2H); 3.00-3.16 (2H); 3.29-3.66 (14H); 4.16-4.22 (0.65H); 4.25-4.30 (0.35H); 7.74 (0.65H); 7.86 (3H); 8.10 (0.35H).

LC / MS (ESI): 528.4; (calculated ([M + H] ⁺ ): 528.4).

Example AA12: AA12 molecule

Molecule A25: Product obtained by the reaction between the molecule B4 and Bocethylenediamine.

By a process similar to that used for the preparation of the molecule A23 applied to the molecule B4 (12.00 g, 40.35 mmol) and to Boc-ethylenediamine (7.76 g, 48.42 mmol) , a colorless oil is obtained and used without further purification.

Yield: 17.40 g (94%)

1H NMR (CDCh, ppm): 0.86 (3H); 1.11-1.68 (18H); 1.41 (9H); 1.80-2.38 (6H); 3.06-3.35 (4H); 3.37-3.49 (1H); 3.51-3.73 (1H); 4.26-4.31 (0.1H); 4.45-4.52 (0.9H); 4.91-5.19 (1H); 6.97 (0.1H); 7.23 (0.9H) .LC / MS (ESI): 440.4 (calculated ([M + H] ⁺ ): 440.3).

AA12 molecule After a process similar to that used for the preparation of the AAI molecule applied to the A25 molecule (8.85 g, 20.13 mmol), a white solid of AA12 molecule is obtained after basic washing, concentration under reduced pressure then recrystallization from acetonitrile.

Yield: 6.53 g (96%)

1H NMR (DMSO, ppm): 0.85 (3H); 1.07-1.56 (20H); 1.68-2.03 (4H); 2.09-2.29 (2H); 2.50-2.58 (2H); 2.96-3.11 (2H); 3.21-3.59 (2H); 4.17-4.21 (0.65H); 4.25-4.29 (0.35H); 7.68 (0.65H); 8.00 (0.35H)

LC / MS (ESI): 340.3; (calculated ([M + H] ⁺ ): 340.3).

Example AA13: AA13 molecule

Molecule A26: Product obtained by coupling between the molecule B1 and Bocethylenediamine.

By a process similar to that used for the preparation of the molecule A23 applied to the molecule B1 (30.00 g, 111.36 mmol) and to Boc-ethylenediamine (21.41 g, 133.64 mmol) , a white solid is obtained after recrystallization from acetonitrile.

Yield: 34.90 g (76%)

1H NMR (CDCh, ppm): 0.88 (3H); 1.10-1.70 (14H); 1.43 (9H); 1.80-1.91 (1H); 1.92-2.01 (1H); 2.04-2.42 (4H); 3.13-3.70 (6H); 4.27-4.31 (0.15H); 4.47-4.53 (0.85H); 4.83 (0.15H); 5.02 (0.85H); 6.85 (0.151-1); 7.21 (0.85H).

LC / MS (ESI): 412.2; (calculated ([M + H] ⁺ ): 412.3).

AA13 molecule After a process similar to that used for the preparation of the AAI molecule applied to the A26 molecule (34.90 g, 84.79 mmol), a white solid of AA13 molecule in the form of the hydrochloride salt is obtained after solubilization in a DCM / acetonitrile mixture and concentration under reduced pressure.

Yield: 29.50 g (99%)

1H NMR (DMSO, ppm): 0.85 (3H); 1.07-1.61 (14H); 1.70-2.06 (4H); 2.10-2.35 (2H); 2.76-2.87 (2H); 3.24-3.47 (3.25H); 3.56-3.64 (0.75H); 4.13-4.19 (0.75H); 4,314.36 (0.25H); 8.05-8.36 (3.75H); 8.50 (0.25H).

LC / MS (ESI): 312.2; (calculated ([M + H] ⁺ ): 312.3).

Free AA14: AA14 molecule

Molecule A27: Product obtained by hydrogenation of phytol.

To a solution of phytol (30.00 g, 101.20 mmol) in THF (450 mL) under argon is added platinum oxide (PtCh, 1.15 g, 6.61 mmol) and the medium is placed under 1 bar of dihydrogen then stirred for 4 h at room temperature. After filtration on celite by rinsing with THF, a black oil of molecule A27 is obtained by concentration under reduced pressure.

Yield: 29.00 g (96%)

NMR ^X H (CDCl₃, ppm): 0.84 (6H); 0.86 (6H); 0.89 (3H); 1.00-1.46 (22H); 1.46-1.68 (3H); 3.61-3.73 (2H).

Molecule A28: Product obtained by oxidation of the molecule A27 [000453] To a solution of molecule A27 (29.0 g, 97.13 mmol) in a dichloroethane / water mixture (485 mL / 388 mL) are successively added bromide of tetrabutylammonium (16.90 g, 52.45 mmol), acetic acetide (150 mL, 2.62 mol) then KMnCU (46.05 g, 291.40 mmol) in small fractions maintaining the temperature between 16 and 19 ° C. The reaction medium is then stirred for 4 h 30 at reflux, cooled to 10 ° C. and then acidified to pH 1 with a 6N HCl solution (20 mL). Na2SO3 (53.90 g) is gradually added while maintaining the temperature at 10 ° C and the medium is stirred until complete discoloration. Water (200 mL) is added, the phases are separated and the aqueous phase is extracted with DCM (2 x 400 mL). The combined organic phases are washed with an aqueous 10% HCl solution (20 mmL), water (2 x 200 mL), an aqueous solution saturated with NaC! (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A yellow oil of molecule A28 is obtained after purification by flash chromatography (eluent: cyclohexane, AcOEt).

Yield: 28.70 g (94%)

NMR ^X H (CDCl₃, ppm): 0.84 (6H); 0.86 (6H); 0.97 (3H); 1.00-1.41 (20H); 1.52 (1H); 1.96 (1H); 2.14 (1H); 2.35 (1H); 11.31 (1H).

LC / MS (ESI): 311.1 (calculated ([M-H]): 311.3).

A29 molecule: Product obtained by coupling between the A28 molecule and methyl L-prolinate.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule A28 (18.00 g, 57.59 mmol) and to methyl L-prolinate hydrochloride (14.31 g, 86, 39 mmol), a yellow oil of molecule A29 is obtained after washing the organic phase with a saturated aqueous solution of NaHCO3 (2 x 150 mL), an aqueous solution of 10% HCl (2 x 150 mL), an aqueous solution saturated with NaCl (2 x 150 mL), then drying over Na2SO4, filtration and concentration under reduced pressure.

Yield: 23.20 g (95%)

^X H NMR (DMSO-d, ppm): from 0.78 to 0.89 (15H); 0.97-1.43 (20H); 1.43-1.56 (1H); 1.701.96 (4H); 1.96-2.32 (3H); 3.33-3.56 (2H); 3.59 (0.6H); 3.67 (2.4H); 4.27 (0.8H); 4.57 (0.2H).

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

A30 molecule: Product obtained by the saponification of the A29 molecule.

By a process similar to that used for the preparation of the molecule A21 applied to the molecule A29 (21.05 g, 49.68 mmol), a yellow oil of molecule A30 is obtained.

Yield: 20.40 g (99%)

^X NMR (DMSO-de, ppm): 0.77 to 0.91 (15H); 0.97-1.43 (20H); 1.43-1.56 (1H); 1,671.96 (4H); 1.96-2.29 (3H); 3.26-3.56 (2H); 4.20 (0.8H); 4.41 (0.2H).

LC / MS (ESI): 410.3 (calculated ([M + H] ⁺ ): 410.4).

A31 molecule: Product obtained by coupling between the A30 molecule and Boc-1-amino4,7,10-trioxa-13-tridecane amine.

By a process similar to that used for the preparation of the molecule A23 applied to the molecule A30 (8.95 g, 21.85 mmol) and to Boc-l-amino-4,7,10-trioxa13-tridecane amine (8.40 g, 26.21 mmol), a colorless oil of molecule A31 is obtained after purification by flash chromatography (eluent: DCM, AcOEt, methanol).

Yield: 10.08 g (65%)

¹ H NMR (DMSO-de, ppm): 0.78-0.89 (15H); 0.97-1.43 (29H); 1.43-1.55 (1H); 1,551.66 (4H); 1.71-2.30 (7H); 2.95 (2H); 3.00-3.19 (2H); 3.34-3.58 (14H); 4.17-4.29 (1H); 6.30-6.79 (1H); 7.67 (0.65H); 8.00 (0.351-1).

LC / MS (ESI): 712.6 (calculated ([M + H] ⁺ ): 712.6).

AA14 molecule [000457] After a process similar to that used for the preparation of the AAI molecule applied to the A31 molecule (10.08 g, 14.16 mmol), the residue obtained after concentration under reduced pressure is dissolved in DCM ( 200 mL), the organic phase is washed with a 2N aqueous NaOH solution (2 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A colorless oil of molecule AA14 in the form of neutral amine is obtained.

Yield: 8.23 g (95%)

^X NMR (DMSO-de, ppm): 0.78 to 0.89 (15H); 0.97-1.43 (20H); 1.43-1.69 (6H); 1.692.30 (8H); 2.56 (2H); 2.99-3.19 (2H); 3.31-3.58 (14H); 4.15-4.29 (1H); 7.70 (0.65H); 8.04 (0.35H).

LC / MS (ESI): 612.5 (calculated ([M + H] ⁺ ): 612.5).

AB: Synthesis of co-polyamino acids

Statistical co-polyamino acids of formula VII or VIIa

not" co-polyamino acids carrying carboxylate charges and hydrophobic radicals AB1 ^, ONa ¥ 0 R _1x Y ¥ O H K m J H n X %)

AB 5

AB6 i = 0.05, DP (m + n) = 23

i = 0.025, DP (m + n) = 20

Hy =

Ri = H or pyroglutamate

AB9

AB10 i = 0.12, DP (m + n) = 30

i = 0.08, DP (m + n) = 25

Hy = .NH Ri = CH ₃ -CO- or H or pyroglutamate ^ 0 V ° / X Xc ₁₅ h ₃₁ HAS DRUNK X We have 0 X ^ nh ₂ „H X _χ , Ν Don't '' HF H The ^J H ^J m not 0 X X i = 0.05, DP (m + n) = 23 XX ^H ₂ * X N H X ^c k X-- ^C 15 ^H 31 r A / ,NOT CV X Hy = The J Ri = H or pyroglutamate

AB21

Ri = H or pyroglutamate

Defined co-polyamino acids of formula VII or Vllb:

example number co-polyamino acids carrying carboxylate charges and hydrophobic radicals AB14 We have ; / VS ) X \ ^^ ^C ! ^5:31 AM -, H / ^R N NOT H H vs ^J m i = 0.04, DP (m) = = 25 Ri = H or pyroglutamate

Table le: list of co-polyamino acids synthesized according to the invention.

Part AB: synthesis of co-polyamino acids

Example AB1: Co-polyamino acid AB1 - sodium poly-L-glutamate modified by the molecule AAI and having a number-average molar mass (Mn) of 2900 g / mol

Co-polyamino acid AB1-1: poly-L-glutamic acid of relative number-average molar mass (Mn) 3851 g / mol resulting from the polymerization of y-benzyl-L-glutamate / V-carboxyanhydride initiated by hexylamine [000458 ] In a flask previously dried in an oven, vacuum-placed ybenzyl-L-glutamate / V-carboxyanhydride (89.9 g, 341 mmol) for 30 min, then

Anhydrous DMF (200 mL) is introduced. The mixture is then stirred under argon until complete dissolution, cooled to 4 ° C, then hexylamine (2.05 mL 15.5 mmol) is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days. The reaction medium is then heated at 65 ° C for 2 h, cooled to room temperature then poured dropwise into diisopropyl ether (3 L) with stirring. The white precipitate is recovered by filtration, washed with diisopropyl ether (2 x 200 ml) then dried under vacuum at 30 ° C to give a poly (gamma-benzyl-Lgutamic) acid (PBLG).

To a solution of PBLG (74.8 g) in trifluoroacetic acid (TFA, 340 mL) at 4 ° C is added dropwise a solution of hydrobromic acid (HBr) at 33% in acid acetic (240 mL, 1.37 mol). The mixture is stirred at room temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (4 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed with a 1: 1 (v / v) mixture of diisopropyl ether and water (340 mL) then with water (340 mL).

The solid obtained is then solubilized in water (1.5 L) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by adding water to obtain a final volume of 2.1 L.

The solution is filtered on a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated until a final volume of 1.8 L is obtained.

The aqueous solution is then acidified by adding 37% hydrochloric acid solution until a pH of 2 is reached. After 4 h of stirring, the precipitate obtained is filtered, washed with water (2 x 340 mL) then dried under vacuum at 30 ° C to give a poly-L-glutamic acid of number average molar mass (Mn) 3861 g / mol relative to a polyoxyethylene (PEG) standard.

Co-polyamino acid AB1 [000463] Co-polyamino acid AB1-1 (10.0 g) is dissolved in DMF (700 mL) at 0 ° CA30 ° C-40 ° C and then cooled to 0 ° C. The AAI molecule in the form of the hydrochloride salt (1.64 g, 3.8 mmol) is suspended in DMF (23 mL) and triethylamine (0.39 g, 3.8 mmol) is then added and the mixture is slightly heated with stirring until complete dissolution. To the solution of co-polyamino acid at 0 ° C., / V-methylmorpholine (NMM, 7.6 g, 75 mmol) in DMF (14 mL) and ethyl chloroformate (ECF, 8.2 g, 75 mmol) are added. After 10 min at 0 ° C, the solution containing the AAI molecule is added and the medium maintained at 30 ° C for 2

h. The reaction medium is poured dropwise onto 5.5 L of water containing NaCl at 15% by mass and HCl (pH 2), then left to stand overnight. The precipitate is collected by filtration and dried under vacuum for about 30 min. The white solid obtained is taken up in water (500 mL) and the pH is adjusted to 7 by slow addition of a 1N aqueous NaOH solution. After filtration through a 0.45 μm filter, the clear solution obtained is purified. by ultrafiltration against a 0.9% NaCl solution and then water, until the conductimetry of the permeate is less than 50 pS / cm. After unloading, the solution is filtered through a 0.2 μm filter and stored at 2-8 ° C.

Dry extract: 24.9 mg / g

An average degree of polymerization (DP) of 23 is estimated by NMR ^X H in D2O by comparing the integration of signals from the hydrophobic grafted to the signals from the main chain.

According to the NMR ^X H: i = 0.05

The calculated average molar mass of the co-polyamino acid AB1 is calculated on the basis of the molar masses of the radicals Ri and R2, the aspartate and / or glutamate residues (including an amide bond), the hydrophobic radical, the DS and the DP.

The calculated average molar mass of the co-polyamino acid AB1 is 3945 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2900 g / mol.

Example AB2: Co-polyamnoacid AB2 - sodium poly-L-glutamate modified by the molecule AAI and having a number-average molar mass (Mn) of 3700 g / mol [000464] By a process similar to that used for the preparation of the copolyaminoacideABl applied to se! of hydrochloride of the molecule AAI (1.64 g, 3.8 mmol) and to a poly-L-glutamic acid of relative Mn 5200 g / mol (10.0 g) obtained by a process similar to that used for the preparation from AB1-1 co-polyamino acid, a sodium poly-L-glutamate modified by the AAI molecule is obtained.

Dry extract: 14.1 mg / g

DP (estimated by NMR ^X H): 35

According to the NMR ^X H: i = 0.05

The calculated average molar mass of the AB2 co-polyamino acid is 5972 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3700 g / mol.

Example AB3: Co-polyamino acid AB3 - sodium poly-L-glutamate modified by the molecule AAI and having a number-average molar mass (Mn) of 4900 g / mol [000465] By a process similar to that used for the preparation of the copolyamino acid AB1 applied to the hydrochloride salt of the AAI molecule (3.30 g, 7.6 mmol) and to a poly-L-glutamic acid of average mass in number (Mn) relative 5200 g / mol (10.0 g) obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1, a sodium poly-L-glutamate modified by the molecule AAI is obtained.

Dry extract: 23.4 mg / g

DP (estimated by NMR ^X H): 35

The calculated average molar mass of the AB3 co-polyamino acid is 6594 g / mol.

According to the NMR ^X H: i = 0.10

Aqueous HPLC-SEC (PEG calibrator): Mn = 4900 g / mol.

Example AB4: Co-polyamino acid AB4 - sodium poly-L-glutamate modified by the molecule AA2 and having a number-average molar mass (Mn) of 1800 g / mol [000466] By a process similar to that used for the preparation of the copolyamino acid AB1 applied to the hydrochloride salt of the AA2 molecule (1.09 g, 2.4 mmol) and to a poly-L-glutamic acid of average mass Mn = 5600 g / mol (6.3 g) obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1 but with a step of deprotection of the benzyl esters using trimethylsilane iodide according to the protocol described in the publication J. Am. Chem. Soc. 2000, 122, 26-34 (Subramanian G., et al.), A sodium poly-L-glutamate modified by the molecule AA2 is obtained.

Dry extract: 21.5 mg / g

DP (estimated by NMR ^X H): 35

According to the NMR ^X H: i = 0.052

The calculated average molar mass of the AB4 co-polyamino acid is 6022 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 1800 g / mol.

Example AB5: ABS co-polyamino acid - sodium poly-L-glutamate modified by the molecule AA6 and having a number-average molar mass (Mn) of 2600 g / mol [000467] By a process similar to that used for the preparation of the copolyamino acid AB1 applied to the hydrochloride salt of the molecule AA6 (2.06 g, 3.8 mmol) and to a poly-L-glutamic acid (9.8 g) obtained by a process similar to that used for the preparation of co -polyamino acid AB1-1, a sodium poly-L-glutamate modified by the molecule AA6 is obtained.

Dry extract: 20.9 mg / g

DP (estimated by NMR ^X H): 23

According to ¹ H NMR: i = 0.05

The calculated average molar mass of AB5 co-polyamino acid is 4079 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2600 g / mol.

Example AB6: Co-polyamino acid AB6 - sodium poly-L-glutamate modified by the molecule AA7 and having a number average molar mass (Mn) of 4000 g / mol [000468] A poly-L-glutamic acid of average mass Mn = 3500 g / mol and degree of polymerization 22 (10.0 g) obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1 is dissolved in DMF (420 mL) at 3040 ° C and then maintained at this temperature. In parallel, the hydrochloride salt of the molecule AA7 (1.47 g, 2.3 mmol) is suspended in DMF (12 mL) and triethylamine (0.23 g, 2.3 mmol) is added , then the mixture is slightly heated with stirring until complete dissolution. To the solution of co-polyamino acid in DMF, NMM (7.6 g, 75 mmol), the solution of AA7 then 2-hydroxypyridine / V-oxide (HOPO, 0.84 g, 7.5 mmol) are added successively. The reaction medium is then cooled to 0 ° C., then EDC (1.44 g, 7.5 mmol) is added and the medium is brought up to ambient temperature for 2 h. The reaction medium is filtered through a 0.2 mm woven filter and poured dropwise onto 3.5 L of water containing NaCl at% by mass and HCl (pH 2) with stirring. At the end of the addition, the pH is readjusted to 2 with a 37% HCl solution, and the suspension is left to stand overnight. The precipitate is collected by filtration, then rinsed with 100 ml of water. The white solid obtained is dissolved in 500 ml of water by slow addition of a 1N aqueous NaOH solution to pH 7 with stirring, then the solution is filtered through a 0.45 μm filter. The clear solution obtained is 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 solution is filtered through a 0.2 µm filter and stored at 2-8 ° C.

Dry extract: 21.6 mg / g

DP (estimated from ¹ H NMR): 20

According to the NMR ^: 1 = 0.025

The calculated average molar mass of the AB6 co-polyamino acid is 3369 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4000 g / mol.

Example AB7: Co-polyamino acid AB7 - sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule AA7 and having a number-average molar mass (Mn) of 3300 g / mol [000469] Co-polyamino acid AB7-1: poly-L-glutamic acid of average molar mass in number (Mn) relative 3600 g / mol and of DP 21 resulting from the polymerization of γ-benzyl-L-glutamate / V-carboxyanhydride initiated by l hexylamine and capped at one of its ends by an acetyl group [000470] In a flask previously dried in an oven is placed under vacuum of ybenzyl-L-glutamate / V-carboxyanhydride (Glu (OBn) -NCA, 100 , 0 g, 380 mmol) for 30 min then anhydrous DMF (225 mL) is introduced. The mixture is then stirred under argon until complete dissolution, cooled to 4 ° C, then hexylamine (1.78 g, 17 mmol) is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days then precipitated in diisopropyl ether (3.4 L). The precipitate is recovered by filtration, washed twice with diisopropyl ether (225 mL) then dried to give a white solid which is dissolved in 450 mL of THF. To this solution are successively added DIPEA (31 mL, 176 mmol) and then acetic anhydride (17 mL, 176 mmol). After stirring overnight at room temperature, the solution is poured slowly into diisopropyl ether (3 L) with stirring. After 1 h of stirring, the precipitate is filtered, washed twice with diisopropyl ether (250 mL) then dried under vacuum at 30 ° C to give a poly (gamma-benzyl-L-glutamic acid) capped at one of its ends by an acetyl group.

To a solution of the above co-polyamino acid (72 g) in trifluoroacetic acid (TFA, 335 mL) at 4 ° C is added dropwise a 33% hydrobromic acid solution (HBr) in acetic acid (235 mL). The mixture is stirred at room temperature for 3 h 30, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (4 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed with a 1: 1 (v / v) mixture of diisopropyl ether and water (340 mL) then with water (340 mL).

The solid obtained is then solubilized in water (1.5 L) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the solution is diluted by adding water to obtain a final volume of 2.1 L. The solution is filtered on a 0.45 μm filter then purified by ultrafiltration against a 0.9% NaCl solution, then water until that the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated until a final volume of 1.8 L is obtained.

The aqueous solution is then acidified by adding 37% hydrochloric acid solution until a pH of 2 is reached. After 4 h of stirring, the precipitate obtained is filtered, washed with water (330 mL ) then dried under vacuum at 30 ° C. to give a poly-L-glutamic acid of number average molar mass (Mn) 3600 g / mol relative to a polyoxyethylene (PEG) standard, and of average degree of polymerization 21.

Co-polyamino acid AB7:

By a process similar to that used for the preparation of copolyamino acid AB6 applied to the hydrochloride salt of the molecule AA7 (1.43 g, 2.2 mmol) and to the co-polyamino acid AB7-1 (10.0 g) , a sodium poly-L-glutamate acid modified by the molecule AA7 is obtained.

Dry extract: 24.3 mg / g

DP (estimated from NMR ^): 21

According to the NMR ^: 1 = 0.03

The calculated average molar mass of the AB7 co-polyamino acid is 3677 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / mol.

Example AB8: Co-polyamino acid AB8 - sodium poly-L-glutamate modified by the molecule AA7 and having a number-average molar mass (Mn) of 3600 g / mol [000475] Co-polyamino acid AB8-1: poly-L acid -glutamic acid of average molar mass in number (Mn) 3800 g / mol and of degree of polymerization 24 resulting from the polymerization of γ-methyl-L-glutamate / V-carboxyanhydride initiated by ammonia [000476] By a process similar to that described in patent application FR-A-2 801 226 applied to γ-methyl-L-glutamic acid / V-carboxyanhydride (25.0 g, 133.6 mmol) and to a 0.5 N ammonia solution in dioxane (12.1 mL, 6.05 mmol), a poly-L-glutamic acid is obtained.

ABS co-polyamino acid:

By a process similar to that used for the preparation of the copolyamino acid AB6 applied to the hydrochloride salt of the molecule AA7 (2.1 g, 3.24 mmol) and to the co-polyamino acid AB8-1 (14.3 g) , a sodium poly-L-glutamate modified by the molecule AA7 is obtained.

Dry extract: 25.2 mg / g

PD (estimated from N NMR): 24

According to the NMR ^: 1 = 0.03

The calculated average molar mass of the AB8 co-polyamino acid is 4099 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3600 g / mol.

Example AB9: Co-polyamino acid AB9 - sodium poly-L-glutamate modified by the molecule AA3 and having a number-average molar mass (Mn) of 3200 g / mol [000478] By a process similar to that used for the preparation of the copolyamino acid ABl applied to the hydrochloride salt of the molecule AA3 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1, a sodium poly-L-glutamate modified by the molecule AA3 is obtained.

Dry extract: 14.7 mg / g

100

DP (estimated by NMR ^X H): 30

According to the NMR ^X H: i = 0.12

The calculated average molar mass of the AB9 co-polyamino acid is 6192 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3200 g / mol.

Example AB1O: Co-polyamino acid AB10 - sodium poly-L-glutamate modified by the molecule AA4 and having a number-average molar mass (Mn) of 2600 g / mol [000479] By a process similar to that used for the preparation of the copolyamino acid AB7 applied to the hydrochloride salt of the molecule AA4 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1, a sodium poly-L-glutamate modified by the AA4 molecule is obtained.

Dry extract: 18.3 mg / g

DP (estimated by NMR ^X H): 25

According to the NMR ^X H: i = 0.08

The calculated average molar mass of the AB10 co-polyamino acid is 4870 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2600 g / mol.

ABU example; ABU co-polyamino acid - sodium poly-L-glutamate modified by the molecule AA5 and having a number-average molar mass (Mn) of 2700 g / mol [000480] By a process similar to that used for the preparation of the copolyamino acid AB6 applied to the hydrochloride salt of the molecule AA5 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1, a sodium poly-L-glutamate modified by the molecule AA5 is got.

Dry extract: 20.2 mg / g

DP (estimated by NMR ^X H): 23

According to the NMR ^X H: i = 0.05

101

The calculated average molar mass of the ABU co-polyamino acid is 4072 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2700 g / mol.

Example AB12: Co-polyamino acid AB12 - sodium poly-L-glutamate modified by the molecule AA8 and having a number-average molar mass (Mn) of 3000 g / mol [000481] By a process similar to that used for the preparation of the copolyamino acid AB1 applied to the hydrochloride salt of the molecule AA8 and to a poly-L-giutamic acid obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1, a sodium poly-L-glutamate modified by the AA8 molecule is obtained.

Dry extract: 19.5 mg / g

DP (estimated by NMR ^X H): 26

According to the NMR ^X H: i = 0.04

The calculated average molar mass of the AB12 co-polyamino acid is 4477 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3000 g / mol.

Example AB13: Co-polyamino acid AB13 - sodium poly-L-glutamate modified by the molecule AA9 and having a number-average molar mass (Mn) of 3300 g / mol [000482] By a process similar to that used for the preparation of the copolyamino acid AB6 applied to the hydrochloride salt of the molecule AA9 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1 using isoamylamine as initiator in place of hexylamine, a sodium poly-L-glutamate modified by the molecule AA9 is obtained.

Dry extract: 22.3 mg / g

DP (estimated by NMR ^X H): 35

According to the NMR ^X H: i = 0.12

The calculated average molar mass of the AB13 co-polyamino acid is 7226 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / mol.

102

Example AB21: Co-polyamino acid AB21 - sodium poly-L-glutamate modified by the molecule AA7 and having a number-average molar mass (Mn) of 3400 g / mol [000483] By a process similar to that used for the preparation of the copolyamino acid AB6 applied to the hydrochloride salt of the molecule AA7 (2.44 g, 2.4 mmol) and to a poly-L-glutamic acid (10 g) obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1, a sodium poly-L-glutamate modified by the molecule AA7 is obtained.

Dry extract: 22.7 mg / g

DP (estimated by NMR ^X H): 22

According to the NMR ^X H: i = 0.056

The calculated average molar mass of the AB21 co-polyamino acid is 4090 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3400 g / mol.

Example AB22: Co-polyamino acid AB22 - sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule AA10 and having a number-average molar mass (Mn) of 4000 g / mol [000484] The hydrochloride salt of the molecule AA10 (4.55 g, 11.29 mmol) is dissolved in chloroform (50 ml) and triethylamine (1.14 g, 11.29 mmol) is added. To a solution of co-polyamino acid (10.0 g, 75.3 mmol) obtained according to a process similar to that used for the preparation of co-polyamino acid B7-1 in DMF (420 mL), NMM (7, 6 g, 75.26 mmol), then HOPO (2.51 g, 22.58 mmol) are added successively. The reaction medium is then cooled to 0 ° C, then EDC (4.33 g, 22.58 mmol) is added, the medium is stirred for 1 hour at 0 ° C then the solution of molecule AA10 is added. The reaction mixture is stirred for 2 h between 0 ° C and room temperature. The reaction medium is filtered through a 0.2 mm woven filter and poured dropwise onto 3.95 L of water containing NaCl at 15% by mass and HCl (pH 2) with stirring. At the end of the addition, the pH is readjusted to 2 with a 37% HCl solution, and the suspension is left to stand overnight. The precipitate is collected by filtration, then dissolved in 780 ml of water by slow addition of a 1N aqueous NaOH solution to pH 7 with stirring. After filtration on a 0.45 μm filter, the solution is diluted by addition

103 of water and then acetone is added to obtain a solution containing 30% by mass of acetone. This solution is filtered on an activated carbon filter and then the acetone is distilled (40 ° C, 100 mbar). After filtration through a 0.45 μm filter, the product is purified by ultrafiltration against a 0.9% aqueous NaCl solution, a carbonate buffer solution (150 mM), a 0.9% aqueous NaCl solution, a solution of phosphate buffer (150 mM), a 0.9% aqueous NaCl solution, then water until the conductimetry of the permeate is less than 50 pS / cm. The solution is then concentrated, filtered through a 0.2 μm filter and stored at 2-8 ° C.

Dry extract: 19.7 mg / g

DP (estimated by NMR ^X H): 38

According to the NMR ^X H: i = 0.16

The calculated average molar mass of the AB22 co-polyamino acid is 7877 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 4000 g / mol.

Example AB23: Co-polyamino acid AB23 - sodium poly-L-glutamate and modified by the molecule AA10 and having a number-average molar mass (Mn) of 7600 g / mol [000485] Cp ^ pqjyamLnojgci ^ poly-L-glutamic acid resulting from the polymerization of y-benzyl-L-glutamate / V-carboxyanhydride initiated by hexylamine and capped at one of its ends by a pyroglutamate group [000486] A poly-L-glutamic acid (20.0 g) obtained by a process similar to that used for the preparation of the co-polyamino acid AB1-1 is dissolved in DMF at 80 ° C. and then maintained at this temperature. After 24 h, the reaction medium is poured into a 15% NaCl solution at pH 2. After 4 h, the white solid is collected by filtration, rinsed with water, then dried under vacuum at 30 ° C.

Co-polyaminoamide AB23 [000487] By a process similar to that used for the preparation of copolyamino acid AB22 applied to the hydrochloride salt of the molecule AA10 (2.742 g, 6.79 mmol) and to the co-polyamino acid AB23-1 (9.0 g), a sodium poly-L-glutamate acid modified with the molecule AA10 is obtained.

Dry extract: 21.9 mg / g

104

DP (estimated from NMR: 60

According to the NMR ^T H: i = 0.1

The calculated average molar mass of the AB23 co-polyamino acid is 11,034 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 7600 g / mol.

Example AB24: Co-polyamino acid AB24 - sodium poly-L-glutamate and modified by the molecule AA10 and having a number-average molar mass (Mn) of 4300 g / mol [000488] By a process similar to that used for the preparation copolyamino acid AB23 applied to the hydrochloride salt of the molecule AA10 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of co-polyamino acid AB23-1, a sodium poly-L-glutamate modified by the AA10 molecule is obtained.

Dry extract: 22.9 mg / g

DP (estimated from NMR ^): 39

According to the NMR ^: 1 = 0.15

The calculated average molar mass of the AB24 co-polyamino acid is 7870 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 4300 g / mol.

Example AB25: Co-polyamino acid AB25 - sodium poly-L-glutamate and modified by the molecule AA10 and having a number-average molar mass (Mn) of 4200 g / mol [000489] By a process similar to that used for the preparation copolyamino acid AB23 applied to the hydrochloride salt of the molecule AA10 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of co-polyamino acid AB23-1, a modified sodium poly-L-glutamate by the molecule AA10 is obtained.

Dry extract: 25.9 mg / g

PD (estimated from N NMR): 39

According to the NMR ^: 1 = 0.2

105

The calculated average molar mass of the co-polyamino acid AB25 is 8509 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 4200 g / mol.

Example AB26: Co-polyamino acid AB26 - sodium poly-L-glutamate and modified by the molecule AA10 and having a number-average molar mass (Mn) of 2700 g / mol [000490] By a process similar to that used for the preparation copolyamino acid AB23 applied to the hydrochloride salt of the molecule AA10 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of co-polyamino acid AB23-1, a modified sodium poly-L-glutamate by the molecule AA10 is obtained.

Dry extract: 23.9 mg / g

DP (estimated from ¹ H NMR): 22

According to the NMR ^X H: i - 0.21

The calculated average molar mass of the AB26 co-polyamino acid is 4899 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn ~ 2700 g / mol.

Example AB27: Co-polyamino acid AB27 - sodium poly-L-glutamate and modified by the molecule AA11 and having a number-average molar mass (Mn) of 4500 g / mol [000491] By a process similar to that used for the preparation copolyamino acid AB23 applied to the hydrochloride salt of the molecule AA11 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of co-polyamino acid AB23-1, a modified sodium poly-L-glutamate by the molecule AA11 is obtained.

Dry extract: 26.8 mg / g

DP (estimated by NMR ^X H): 39

According to the NMR ^X H: i = 0.15

The calculated average molar mass of the AB27 co-polyamino acid is 8808 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 4500 g / mol.

106

Example AB28: Co-polyamino acid AB28 - sodium poly-L-glutamate and modified by the molecule AA12 and having a number-average molar mass (Mn) of 4000 g / mol [000492] By a process similar to that used for the preparation copolyamino acid AB23 applied to the hydrochloride salt of the molecule AA12 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of co-polyamino acid AB23-1, a modified sodium poly-L-glutamate by the molecule AA12 is obtained.

Dry extract: 22.9 mg / g

DP (estimated by NMR ^X H): 39

According to the NMR ^X H: i = 0.15

The calculated average molar mass of the AB28 co-polyamino acid is 7706 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 4000 g / mol.

Example AB29: Co-polyamino acid AB29 - sodium poly-L-glutamate and modified by the molecule AA13 and having a number-average molar mass (Mn) of 4000 g / mol [000493] Co-polyamino acid B29-1: poly- L-glutamic resulting from the polymerization of γ-benzyl-L-glutamate / V-carboxyanhydride initiated by hexylamine

In a jacketed reactor, γ-benzyl-L-glutamate / V-carboxyanhydride (500 g, 1.90 mol) is dissolved in anhydrous DMF (1100 mL). The mixture is then stirred until complete dissolution, cooled to 0 ° C, then hexylamine (6.27 mL, 47.5 mmol) is introduced quickly. The mixture is stirred at 0 ° C for 5 h, between 0 ° C and 20 ° C for 7 h, then at 20 ° C for 7 h. The reaction medium is then heated to 65 ° C for 2 h, cooled to 55 ° C and methanol (3300 mL) is introduced in 1 h 30 min. The reaction mixture is then cooled to 0 ° C and left to stir for 18 h . The bianc precipitate is recovered by filtration, washed with diisopropyl ether (2 x 800 mL) and then dried under reduced pressure at 30 ° C to give a poly (gamma-benzyl-Lglutamic acid) (PBLG).

To a solution of PBLG (180 g) in / V, / V-dimethylacetamide (DMAc, 450 mL) is added Pd / AbO3 (36 g) under an argon atmosphere. The mixture is placed under

107 hydrogen atmosphere (10 bar) and stirred at 60 ° C for 24 h. After cooling to room temperature and filtration of the catalyst on a sintered P4 then on a 0.2 μm hydrophilic PTFE Omnipore membrane, a solution of water at pH 2 (2700 mL) 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 at 30 ° C.

Co-polyamino acid AB29 [000494] By a process similar to that used for the preparation of copolyamino acid AB23 applied to itself! hydrochloride of the molecule AA13 and copolyamino acid AB29-1, a sodium poly-L-glutamate modified by the molecule AA13 is obtained.

Dry extract: 16.1 mg / g

DP (estimated by NMR ^X H): 40

According to NMR = 0.15

The calculated average molar mass of the AB29 co-polyamino acid is 7734 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 4000 g / mol.

Example AB30: Co-polyamino acid AB30 - sodium poly-L-glutamate and modified by the molecule AA10 and having a number-average molar mass (Mn) of 4300 g / mol [000495] By a process similar to that used for the preparation copolyamino acid AB29 applied to the hydrochloride salt of the molecule AA10 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of the co-polyamino acid AB29-1 using the molecule AA10 as initiator in place of hexylamine, a sodium poly-L-glutamate modified by the molecule AA10 is obtained.

Dry extract: 29.2 mg / g

DP (estimated from NMR * H): 40

According to the NMR ^: 1 = 0.125

The calculated average molar mass of the AB30 co-polyamino acid is 7682 g / mol.

108

Organic HPLC-SEC (PEG calibrator): Mn = 4300 g / mol.

Example AB31: Co-polyamino acid AB3O - sodium poly-L-glutamate and modified by the molecule AA10 and having a number-average molar mass (Mn) of 6300 g / mol [000496] By a process similar to that used for the preparation copolyamino acid AB29 applied to the hydrochloride salt of the molecule AA10 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of the co-polyamino acid AB29-1 using the molecule AA10 as initiator in place of the hexylamine, a sodium poly-L-glutamate modified by the molecule AA10 is obtained.

Dry extract: 23.1 mg / g

DP (estimated by NMR ^X H): 40

According to the NMR ^X H: i = 0.175

The calculated average molar mass of the AB31 co-polyamino acid is 8337 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 6300 g / mol.

Example AB32: Co-polyamino acid AB32 - sodium poly-L-glutamate and modified by the molecule AA14 and having a number-average molar mass (Mn) of 4700 g / mol [000497] By a process similar to that used for the preparation copolyamino acid AB29 applied to the molecule AA14 and to poly-L-glutamic acid AB29-1, a sodium poly-L-glutamate modified by the molecule AA14 is obtained.

Dry extract: 13.5 mg / g

DP (estimated by NMR ^X H): 40

According to the NMR ^X H: i = 0.109

The calculated average molar mass of the AB32 co-polyamino acid is 8599 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 4700 g / mol.

109

Co-polyamino acids of formula VII or Vllb

Example AB14: Co-polyamino acid AB14 - sodium poly-L-glutamate modified at one of its ends by the molecule AAI and having a number-average molar mass (Mn) of 3400 g / mol [000498] A suitable container is introduced successively the hydrochloride salt of the AAI molecule (2.03 g, 4.70 mmol), chloroform (5 mL), 4 Å molecular sieve (1.3 g), as well as Amberlite ion exchange resin IRN 150 (1.3 g). After 1 h of stirring on rollers, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then co-evaporated with toluene. The residue is dissolved in anhydrous DMF (30 mL) to be used directly in the polymerization reaction.

In a balloon previously dried in an oven, γ-benzyl-L-glutamate Ncarboxyanhydride (25.59 g, 97.2 mmol) is placed under vacuum for 30 min and then anhydrous DMF (140 mL) is introduced . The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of AAI molecule prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then heated to 65 ° C for 2 h. The mixture reacts! is then cooled to room temperature then poured dropwise into diisopropyl ether (1.7 L) with stirring. The white precipitate is recovered by filtration, washed twice with diisopropyl ether (140 ml) then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (160 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (62 mL, 354 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (1.9 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with a 1: 1 mixture (v / v) of diisopropyl ether and water (280 ml) then with water (140 ml). The solid obtained is dissolved in water (530 ml) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 theoretical g / L by adding water to obtain a final volume of 800 mL. The mixture is filtered on a 0.45 μm filter and is then purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to

110 approximately 30 g / L theoretical and the pH is adjusted to 7.0. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 24.1 mg / g

DP (estimated by NMR ^X H) = 25 therefore i = 0.04

The calculated average molar mass of the AB14 co-polyamino acid is 3378 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3400 g / mol.

Example AB15: Co-polyamino acid AB15 - sodium poly-L-glutamate modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) 4100 g / mol [000500] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA6 (2.16 g, 3.94 mmol) and to 25.58 g (97.2 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride , a sodium polyL-glutamate modified at one of its ends by the molecule AA6 is obtained.

Dry extract: 45.5 mg / g

DP (estimated by NMR ^X H) = 30 therefore i - 0.033

The calculated average molar mass of the AB15 co-polyamino acid is 5005 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4100 g / mol.

Example AB16: Co-polyamino acid AB16 - sodium poly-L-glutamate modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) of 6500 g / mol [000501] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA6 (2.39 g, 4.36 mmol) and to 50.0 g (189.9 mmol) of γ-benzyl-L-glutamate / V- carboxyanhydride, a sodium polyL-glutamate modified at one of its ends by the molecule AA6 is obtained.

Dry extract: 28.5 mg / g

DP (estimated by NMR ^X H) = 48 therefore i = 0.021

The calculated average molar mass of the AB16 co-polyamino acid is 7725 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 6500 g / mol.

111

Example AB17: Co-polyamino acid AB17 - sodium poly-L-glutamate modified at one of its ends by the molecule AA7 and having a number-average molar mass (Mn) of 3500 g / mol [000502] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA7 (2.80 g, 4.32 mmol) and to 25.0 g (94.9 mmol) of γ-benzyl-L-glutamate / V- carboxyanhydride, a sodium polyL-glutamate modified at one of its ends by the molecule AA7 is obtained.

Dry extract: 25.2 mg / g

DP (estimated by ¹ H NMR) = 26 therefore i = 0.038

The calculated average molar mass of AB17 co-polyamino acid is 4500 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3500 g / mol.

Example AB18: Co-polyamino acid AB18 - sodium poly-L-glutamate modified at one of its ends by the molecule AA7 and having a number-average molar mass (Mn) of 3700 g / mol [000503] A poly-L-glutamate sodium modified at one of its ends by the molecule AA7 is obtained by polymerization of γ-methyl / V-carboxyanhydride of glutamic acid (25.0 g, 133.6 mmol) using the hydrochloride salt of the molecule AA7 (2 , 80 g, 4.32 mmol) as initiator and by deprotecting the methyl esters by using a 37% hydrochloric acid solution according to the process described in patent application FR-A-2 801 226.

Dry extract: 44.3 mg / g

DP (estimated by NMR ^X H) = 22 therefore i = 0.045

The calculated average molar mass of the AB18 co-polyamino acid is 3896 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3700 g / mol.

112

Example AB19: Co-polyamino acid AB19 - sodium poly-L-glutamate modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) of 10500 g / mol [000504] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA6 (1.64 g, 2.99 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (49.3 g, 187 mmol), a sodium polyL-glutamate modified at one of its ends by the molecule AA6 is obtained.

Dry extract: 23.4 mg / g

DP (estimated by NMR ^X H) = 65 therefore i = 0.015

The calculated average molar mass of the AB19 co-polyamino acid is 10293 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 10,500 g / mol.

Example AB20: Co-polyamino acid AB20 - sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) of 10,400 g / mol [000505] In a suitable container are successively introduced the hydrochloride salt of the molecule AA6 (0.545 g, 1.00 mmol), chloroform (10 mL), molecular sieve 4 Â (3 g), as well as Amberlite IRN 150 ion exchange resin (3 g). After 1 h of stirring on rollers, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then co-evaporated with toluene. The residue is dissolved in anhydrous DMF (10 mL) to be used directly in the polymerization reaction.

In a balloon previously dried in an oven, γ-benzyl-L-glutamate Ncarboxyanhydride (17.0 g, 64.6 mmol) is placed under vacuum for 30 min and then anhydrous DMF (30 mL) is introduced . The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of molecule AA6 prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then precipitated in diisopropyl ether (0.6 L). The precipitate is recovered by filtration, washed twice with diisopropyl ether (40 ml) then dried to give a white solid which is dissolved in 80 ml of THF. To this solution are successively added DIPEA (1.7 mL, 9.8 mmol) and then acetic anhydride (0.9 mL, 9.5 mmol). After stirring overnight at room temperature, the solution is poured slowly into diisopropyl ether (480 mL) over a

113 duration of 30 min and with stirring. After 1 h of stirring, the precipitate is filtered, washed twice with diisopropyl ether (80 mL) then dried under vacuum at 30 ° C to give a poly (gamma-benzyl-L-glutamic acid) capped at one of its ends by an acetyl group and modified at the other of its ends by the molecule AA6 in the form of a white solid.

The solid is diluted in TFA (65 mL), and a solution of hydrobromic acid (HBr) at 33% in acetic acid (45 mL, 257.0 mmol) is then added dropwise and at 4 ° C. The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (780 mL). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with a 1: 1 (v / v) mixture of diisopropyl ether and water (70 mL) then with water (70 mL). The solid obtained is dissolved in water (300 ml) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by adding water to obtain a final volume of 440 mL. The mixture is filtered on a 0.45 μm filter and is then purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to 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: 21.5 mg / g

DP (estimated by NMR ^) = 60 therefore i = 0.017

The calculated average molar mass of AB20 co-polyamino acid is 9619 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 10400 g / mol.

Part B:

BB: synthesis of hydrophobic molecules in which p = 2 The radicals are represented in the following table by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.

114

No. Structure of the hydrophobic molecule before grafting on the co-polyamino acid BAI oAh ° 1 HA ^CsH « ^H * ^N 0 BA2 O ^ ²³ O ^ NH \ Y ' ^f H, N' ^ X / ^NH X \ _Kh A ^{c h} ' ^{! z} rr nh \ q O BA3 Xx ^ / ^Cl3H2 7 Y Ίί A ° XX \ Oy Η ₂ Ν ^ · ^ΝΗ γΧΛ _ο ^C ” ^H27 O

115

BA4 / X, 0 o ^: N Υι ₃ Η ₂₇ YY J 0 ^x NH \ (i »I V ^ nh '' 0 C ₁₃ H ₂₇ Υί LOW / \ Yl5 ^H 31 V 1 ® ο O ^ NH 1 s r " - "" Ί. 1 \ χ / L - ° YY NN ^ XX ^{H 2} r O Yh ^x c ₁₅ h ₃₁ X ·. Ό BA6 ï n ^ Y 0 ^1:27 p.m. 0 ^ '' NH H ₂ N ' MH i Ο * -γ ° Y. θ13 ^Η 27 'NH X ₀ 0

116

Table 1d: list of hydrophobic molecules synthesized according to the invention.

Part BA: synthesis of hydrophobic molecules in which p = 2

BAI example: BAI molecule

Molecule B1: Product obtained by the reaction between decanoic acid and L-proline.

Dicyclohexyl carbodiimide (DCC) (16.29 g, 78.96) are successively added to a solution of decanoic acid (14.28 g, 82.91 mmol) in THF (520 mL) at 0 ° C mmol) and / V-hydroxysuccinimide (NHS) (9.09 g, 78.96 mmol). After 60 h of stirring at room temperature, the medium is cooled to 0 ° C for 20 min, filtered through 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 ethyl acetate (2 x 250 mL), acidified to pH ~ 1 with a 1N aqueous HCl solution and then extracted with dichloromethane (3 x 150 mL). The combined organic phases are dried over NaiSCk, filtered, concentrated in vacuo and the residue is purified by chromatography on silica gel (cyclohexane, ethyl acetate).

Yield: 14.6 g (69%)

NMR ^X H (CDCl₃, ppm): 0.87 (3H); 1.26 (12H); 1.65 (2H); 2.02 (3H); 2.34 (2H); 2.41 (1H); 3.48 (1H); 3.56 (1H); 4.58 (1H).

LC / MS (ESI): 270.2; (calculated ([M + H] ⁺ ): 270.4).

117

Molecule B2: Product obtained by the reaction between the molecule B1 and L-lysine.

By a process similar to that used for the preparation of the B1 molecule applied to the B1 molecule (14.57 g, 54.07 mmol) and to L-iysine (4.15 g, 28.39 mmol) , a yellow oil is obtained.

Yield: 16.4 g (93%)

NMR ^X H (CDCl₃, ppm): 0.88 (6H); 1.26 (24H); 1.35-1.65 (8H); 1.85-2.35 (12H); 2.53 (0.2H); 2.90 (0.8H); 3.45-3.75 (5H); 4.50-4.70 (3H); 7.82 (1H).

LC / MS (ESI): 649.6; (calculated ([M + H] ⁺ ): 649.9).

Molecule B3: Product obtained by reaction between the molecule B2 and Bocethylenediamine.

To a solution of molecule B2 (16.4 g, 25.27 mmol) in THF (170 mL) are added DIPEA (8.80 mL) and 2- (1H-benzotriazol-l-yl ) -1,3,3tetramethyluronium tetrafluoroborate (TBTU, 8.52 g, 26.54 mmol) at room temperature. After 30 min of stirring, Sa Boc-ethylenediamine (4.45 g, 27.8 mmol) is added. After stirring at room temperature for 2 h, the solvent is evaporated off under reduced pressure and the residue is diluted with ethyl acetate (400 ml). The organic phase is washed with water (250 ml), a saturated aqueous solution of NaHCO3 (250 ml), an aqueous solution of 1 N HCl (250 ml), a saturated aqueous solution of NaCI (250 ml) and is dried over Na2SO4. After filtration and concentration under vacuum, the residue obtained is purified by chromatography on silica gel (ethyl acetate, methanol) to give a colorless oil.

Yield: 12.8 g (64%)

1 H NMR (CDCh, ppm): 0.87 (6H); 1.25-1.60 (42H); 1.80-2.05 (4H); 2.15-2.45 (9H); 3.10-3.75 (10H); 4.30 (1H); 4.50 (2H); 5.50 (0.6H); 5.89 (0.2H); 6.15 (0.2H); 7.03 (1H); 7.47 (1H).

LC / MS (ESI): 791.8; (calculated ([M + H] ⁺ ): 792.1).

BAI molecule [000512] To a solution of the molecule B3 (12.78 g, 16.15 mmol) in dichloromethane (110 mL) at 5 ° C is added a solution of 4N HCl in dioxane (20.2 mL ). After 20 h of stirring at 5 ° C, the medium is concentrated in vacuo. The residue

118 obtained is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of BAI molecule in the form of the hydrochloride salt.

Yield: 11.4 g (97%)

¹ H NMR (DMSO-de, ppm): 0.85 (6H); 1.25-1.50 (33H); 1.57 (1H); 1.70-2.40 (12H); 2.82 (2H); 3.00 (2H); 3.25-3.70 (6H); 4.05-4.50 (3H); 7.75-8.45 (6H).

LC / MS (ESI): 691.6; (calculated ([M + H] ⁺ ): 692.0).

Example BA2: BA2 molecule

Molecule B4: Product obtained by the reaction between lauric acid and L-proline.

By a process similar to that used for the preparation of the molecule B1 applied to lauric acid (31.83 g, 157.9 mmol) and to L-proline (20 g, 173.7 mmol), a yellow oil is obtained.

Yield: 34.3 g (73%)

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

LC / MS (ESI): 298.2; (calculated ([M + H] ⁺ ): 298.4).

Molecule B5: Product obtained by the reaction between the molecule B4 and ia L-lysine.

By a process similar to that used for the preparation of the molecule B1 applied to the molecule B4 (33.72 g, 113.36 mmol) and to L-lysine (8.70 g, 59.51 mmol) , a white solid is obtained.

Yield: 26.2 g (66%)

¹ H NMR (CDCh, ppm): 0.88 (6H); 1.26 (32H); 1.35-1.65 (8H); 1.85-2.35 (15H); 2.87 (1H); 3.40-3.75 (5H); 4.50-4.75 (3H); 7.87 (1H).

LC / MS (ESI): 705.6; (calculated ([M + H] ⁺ ): 706.0).

119

B6 molecule: product obtained by reaction between Boc-ethylenediamine and the B5 molecule.

By a process similar to that used for the preparation of the B3 molecule applied to the B5 molecule (25.74 g, 36.51 mmol) and to Boc-ethylenediamine (6.43 g, 40.16 mmol) , a colorless oil is obtained.

Yield: 30.9 g (quantitative)

¹ H NMR (CDCh, ppm): 0.88 (6H); 1.35-1.65 (50H); 1.85-2.35 (13H); 3.05-3.75 (10H); 4.25-4.65 (3H); 5.50 (0.4H); 5.88 (0.2H); 6.16 (0.2H); 7.08 (1H); 7.26 (1H); 7.49 (0.2H).

LC / MS (ESI): 847.8; (calculated ([M + H] ⁺ ): 848.2).

BA2 molecule After a process similar to that used for the preparation of the BAI molecule applied to the B6 molecule (30.9 g, 36.47 mmol), the residue obtained after concentration in vacuo is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of molecule BA2 in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 27.65 g (97%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.10-2.40 (54H); 2.75-3.15 (4H); 3.25-3.60 (6H); 4.05-4.50 (3H); 7.50-8.50 (6H).

LC / MS (ESI): 747.6; (calculated ([M + H] ⁺ ): 748.1).

Example BA3: BA3 molecule

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

By a process similar to that used for the preparation of the molecule B1 applied to myristic acid (18.93 g, 82.91 mmol) and to L-proline (10 g, 86.86 mmol), a yellowish oil is obtained.

Yield: 20 g (78%)

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

120

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

Molecule B8: Product obtained by the reaction between the molecule B7 and L-lysine [000518] By a process similar to that used for the preparation of the molecule B1 applied to the molecule B7 (20.02 g, 61.5 mmol) and with L-lysine (4.72 g, 32.29 mmol), a white solid is obtained.

Yield: 12.3 g (53%)

¹ H NMR (DMSO-d6, ppm): 0.85 (6H); 1.26 (40H); 1.35-1.50 (6H); 1.50-2.10 (10H); 2.10-2.25 (4H); 3.01 (2H); 3.31-3.55 (4H); 4.10-4.40 (3H); 7.68 (0.6H); 7.97 (1H); 8.27 (0.4H); 12.50 (1H).

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

Molecule B9: Product obtained by the reaction between Boc-ethylenediamine and the molecule B8.

By a process similar to that used for the preparation of the molecule B3 applied to the molecule B8 (12 g, 15.77 mmol) and to Boc-ethylenediamine (3.03 g, 18.92 mmol), a colorless oil is obtained after purification by a chromatographic column on silica gel (ethyl acetate, methanol).

Yield: 12.5 g (88%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.20-1.55 (55H); 1.50-2.25 (14H); 2.95-3.10 (6H); 3.31-3.55 (4H); 4.10-4.40 (3H); 6.74 (1H); 7.60-8.25 (3H).

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

BA3 molecule After a process similar to that used for its preparation of the BAI molecule applied to the B9 molecule (12.5 g, 13.84 mmol), the residue obtained after concentration in vacuo is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of BAS molecule in the form of se! hydrochloride after drying under reduced pressure.

Yield: 9.2 g (79%)

^X 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).

121

Example BA4: BA4 molecule

Molecule B_10j. Product obtained by the reaction between the molecule B8 and Boc-1-amino4,7,10-trioxa-13-tridecane amine.

By a process similar to that used for its preparation of the molecule B3 applied to the molecule B8 (29.80 g, 39.15 mmol) and to Boc-l-amino-4,7,10-trioxa13-tridecane amine (15.05 g, 46.96 mmol), a thick colorless oil is obtained.

Yield: 25.3 g (61%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.25-2.35 (75H); 2.85-3.20 (6H); 3.25-3.65 (16H); 4.10-4.45 (3H); 6.38 (0.1H); 6.72 (0.9H); 7.50-8.25 (3H).

LC / MS (ESI): 1064.2; (calculated ([M + H] ⁺ ): 1064.5).

BA4 molecule [000522] After a process similar to that used for the preparation of the BAI molecule applied to the B10 molecule (25.3 g, 23.8 mmol), the residue obtained after concentration in vacuo is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of molecule BA4 in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 20.02 g (84%)

^X NMR (DMSO-de, ppm): 0.85 (6H); 1.15-2.35 (66H); 2.80-3.20 (6H); 3.30-3.65 (16H); 4.10-4.45 (3H); 7.55-8.60 (6H).

LC / MS (ESI): 964.9; (calculated ([M + H] ⁺ ): 964.6).

BAS example: BA5 molecule

Molecule B11: Product obtained by reaction between the molecule Al and L-Lysine [000523] By a process similar to that used for the preparation of the molecule B1 applied to the molecule Al (19.10 g, 54.02 mmol) and with L-lysine (4.15 g, 28.36 mmol), an oily residue is obtained after concentration of the reaction medium under reduced pressure. This residue is diluted in water (150 mL), washed with ethyl acetate (2 x 75 mL) then the aqueous phase is acidified to pH 1 by slow addition of 6N HCl.

122

The product is extracted 3 times with dichloromethane, the organic phase is dried over Na2SO4 then filtered and concentrated under reduced pressure to give 11.2 g of yellow oily residue. In parallel, the preceding ethyl acetate organic phase is washed with an aqueous 2N HCl solution (2 × 75 mL), an aqueous solution saturated with NaCl (75 mL), dried over NazSCU, filtered and concentrated to give 10 , 2 g of yellow oily residue. A white solid is obtained after recrystallization of each of these residues in acetone.

Yield: 11.83 g (54%)

^X H NMR (CDCl _3, ppm): 0.87 (6H); 1.06-2.44 (70H); 2.78-2.96 (1H); 3.35-3.75 (5H); 4.28-4.43 (0.1H); 4.43-4.52 (0.2H); 4.52-4.61 (1.8H); 4.61-4.75 (0.9H); 7,748.02 (2H).

LC / MS (ESI): 818.0; (calculated ([M + H] ⁺ ): 818.7).

B12 molecule: Product obtained by coupling between the Bll molecule and its Bocethylenediamine [000524] By a process similar to that used for the preparation of the B3 molecule applied to the Bll molecule (18.00 g, 22.02 mmol) in solution in THF and Boc-ethylenediamine (4.23 g, 26.43 mmol), a white solid is obtained after recrystallization twice from acetonitrile.

Yield: 17.5 g (83%)

^X H NMR (DMSO-d6, ppm): 0.85 (6H); 1.15-2.29 (79H); 2.92-3.12 (6H); 3.30-3.59 (4H); 4.06-4.13 (0.65H); 4.16-4.29 (2H); 4.38-4.42 (0.35H); 6.71-6.76 (1H); 7,607.69 (1.3H); 7.76-7.81 (0.65H); 7.93-7.97 (0.35H); 8.00-8.04 (0.35H); 8.10-8.17 (0.35H).

LC / MS (ESI): 960.4; (calculated ([M + H] ⁺ ): 960.8).

BAS molecule By a process similar to that used for the preparation of the BAI molecule applied to the B12 molecule (24.4 g, 25.43 mmol), the residue obtained after concentration in vacuo is dissolved in dichloromethane (150 mL), the organic phase is washed twice with a 2N aqueous sodium hydroxide solution (90 mL). Acetonitrile (120 mL) is added and the dichloromethane is removed by concentration under reduced pressure. The medium is then left to stand for 72 h and a white solid is obtained after filtration and rinsing with acetonitrile then drying under reduced pressure. This operation is repeated 4 times.

123

Yield: 14.28 g (65%)

^X H NMR (DMSO-d6, ppm): 0.85 (6H); 1.06-2.32 (70H); 2.53-2.63 (2H); 2.89-3.61 (10H); 4.04-4.43 (3H); 7.55-7.62 (0.65H); 7.65-7.72 (0.65H); 7.80 (0.65H); 7.91 (0.35H); 8.03 (0.35H); 8.14-8.23 (0.351-1).

LC / MS (ESI): 860.0; (calculated ([M + H] ⁺ ): 860.8).

Example BA6: BA6 molecule

Molecule B13: Product obtained by the reaction between / V- (te / t-butoxycarbonyl) -1,6diaminohexane and the molecule B8.

By a process similar to that used for the preparation of the molecule B3 applied to the molecule B8 (10 g, 13.14 mmol) and to / V- (tert-butoxycarbonyl) -1.6diaminohexane (3.41 g , 15.77 mmol) in dichloromethane, a white solid is obtained after recrystallization from acetonitrile.

Yield: 10.7 g (85%)

NMR ^X H (CDCl₃, ppm): 0.88 (6H); 1.17-2.40 (79H); 3.00-3.71 (10H); 4.26-4.58 (3H); 4.67 (1H); 6.74 (1H); 7.34-7.49 (2H).

LC / MS (ESI): 959.9; (calculated ([M + H] ⁺ ): 959.8).

BA6 molecule After a process similar to that used for the preparation of the BAI molecule applied to the B13 molecule (10.5 g, 10.94 mmol), an aqueous solution of NaOH 2 N is added dropwise to the medium reaction cooled to 0 ° C. The aqueous phase is extracted with dichloromethane then the organic phase is washed 3 times with a 5% aqueous NaCl solution. After drying over Na2SO4, the organic phase is filtered, concentrated in vacuo and the residue is recrystallized from acetonitrile.

Yield: 5.4 g (58%)

NMR ^X H (CDCl₃, ppm): 0.88 (6H); 1.19-2.40 (72H); 2.67 (2H); 3.03-3.70 (8H); 4.26-4.57 (3H); 6.71 (1H); 7.39-7.49 (2H).

LC / MS (ESI): 859.8; (calculated ([M + H] ⁺ ): 859.7).

124

Example BA7: BA7 molecule

Molecule B14: Product obtained by coupling between the molecule B7 and 2,3diaminopropionic acid [000528] By a process similar to that used for the preparation of the molecule B1 applied to the molecule B7 (80.00 g, 245.78 mmol ) and with 2,3-diaminopropionic acid dihydrochloride (22.84 g, 129.04 mmol), a white solid is obtained after recrystallization from acetonitrile.

Yield: 69 g (78%)

1 H NMR (DMSO-d6, ppm): 0.86 (6H); 1.08-1.38 (40H); 1.40-1.55 (4H); 1.68-2.30 (12H); 3.16-3.66 (6H); 4.20-4.39 (3H); 7.67-8.31 (2H); 12.70 (1H).

LC / MS (ESI): 719.4; 741.5; (calculated ([M + H] ⁺ ): 719.6; ([M + Na] ⁺ ): 741.6).

Molecule B15: product obtained by coupling between the molecule B14 and Bocethylenediamine [000529] By a process similar to that used for the preparation of the molecule B3 applied to the molecule B14 (32.00 g, 44.50 mmol) in solution in dichloromethane and with Boc-ethylenediamine (8.56 g, 53.40 mmol), a colorless oil is obtained after purification by chromatography on silica gel (ethyl acetate, methanol).

Yield: 24.5 g (64%)

^Χ N NMR (DMSO-d6, ppm): 0.85 (6H); 1.16-2.42 (65H); 2.89-3.14 (4H); 3.17-3.66 (6H); 4.11-4.43 (3H); 6.77 (1H); 7.38-8.23 (3H).

LC / MS (ESI): 861.7; (calculated ([M + HJ +): 861.7).

BA7 molecule [000530] After a process similar to that used for the preparation of the BAI molecule applied to the B15 molecule (24.50 g, 28.45 mmol), the reaction medium is concentrated under reduced pressure, the residue is dissolved in dichloromethane, the organic phase is washed with an aqueous solution of NaOH 2 N), dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid is obtained after recrystallization from acetonitrile.

125

Yield: 19.7 g (91%)

^X H NMR (DMS0-d6, ppm): 0.85 (6H); 1.10-2.40 (58H); 2.51-2.62 (2H); 2.90-3.16 (2H); 3.16-3.67 (6H); 4.04-4.47 (3H); 7.33-8.27 (3H).

LC / MS (ESI): 761.5; (calculated ([M + H] ⁺ ): 761.6).

126

BB ^ Synthesis of coeolyamino ^ cides

ÇçzRolyaminpaçide ^ ^ dedfe

co-polyamino acids carrying carboxylate charges and hydrophobic radicals

BB1

Hy =

O

Ri = H or pyroglutamate

127

BB2

128

BB3

i = 0.049, DP (m + n) = 34

Ri = H or pyroglutamate

129

BB4

i = 0.04, DP (m + n) =

Hy =

Ri = H or pyroglutamate

130

BB5

Rl = CH3-CO-, H or pyroglutamate

131

BB6

Ri

nh ₂

Rl = CH3-CO-, H or pyroglutamate

132

BB7

i = 0.042, DP (m + n) = 22

Ri = H or pyroglutamate

133

BB8

i = 0.026, DP (m + n) = 21

Ri = H or pyroglutamate

134

BB9

i = 0.05, DP (m + n) = 26

Ri = H or pyroglutamate

135

BB10

Ri = H or pyroglutamate

136

BB11

R-ι

O

NOT

H

i = 0.032, DP (m + n) = 22

137

138

Table the

139

Co-polyamino acids of formula VII or Vllb

140

141

BB18

BB19

142

BB20

i = 0.043, DP (m) = 23

Rl = H or pyroglutamate

BB21

i = 0.11, DP (m) = 9

Rl = H or pyroglutamate

143

BB22

i = 0.04, DP (m) = 25

Rl = H or pyroglutamate

BB23

i = 0.048, DP (m) = 21

RI = H or pyroglutamate

144

BB24

C ₁₃ H ₂ 7

i = 0.089, DP (m) = 22

Rl = H or pyroglutamate

145

Table lf: list of co-polyamino acids synthesized according to the invention.

Part BB: synthesis of co-polyamino acids

Example BB1: Co-polyamino acid BB1 - sodium poly-L-glutamate modified by the molecule BA2 and having a number-average molar mass (Mn) of 2400 g / mol

Co-polyamino acid BB1-.1: poly-L-glutamic acid with a number-average molar mass (Mn) relative 3860 g / mol resulting from the polymerization of y-benzyl-L-glutamate 10 / V-carboxyanhydride initiated by hexylamine

146 [000531] In a flask previously dried in an oven is placed under vacuum ybenzyl-L-glutamate / V-carboxyanhydride (90.0 g, 342 mmol) for 30 min, then anhydrous DMF (455 mL) is introduced . The mixture is then stirred under argon until complete dissolution, cooled to 4 ° C, then hexylamine (1.8 mL 14 mmol) is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days. The reaction medium is then heated at 65 ° C for 4 h, cooled to room temperature then poured dropwise into cold diisopropyl ether (6 L) with stirring. The white precipitate is recovered by filtration, washed with diisopropyl ether (500 ml then 250 ml) then dried under vacuum at 30 ° C to give a poly (y-benzyl-L-glutamic acid) (PBLG).

To a solution of PBLG (42.1 g) in trifluoroacetic acid (TFA, 325 mL) at 4 ° C is added dropwise a solution of hydrobromic acid (HBr) at 33% in acid acetic (135 mL, 0.77 mol). The mixture is stirred at ambient temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (1.6 L). After 1 hour 30 minutes of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed with a 1: 1 (v / v) mixture of diisopropyl ether and water (200 mL).

The solid obtained is then solubilized in water (1 L) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 25 g / L theoretical by adding water to obtain a final volume of 1.5 L.

The solution is filtered on a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductimetry of the permeate is less than 50 pS / cm.

The aqueous solution is then acidified by adding 37% hydrochloric acid solution until a pH of 2 is reached. After 4 h of stirring, the precipitate obtained is filtered and then dried under vacuum at 30 ° C to give a poly-L-glutamic acid of number average molar mass (Mn) 3860 g / mol relative to a polyoxyethylene (PEG) standard.

Co-polyamino acid BB1 [000536] The co-polyamino acid BB1-1 (10.0 g) is dissolved in DMF (700 mL) at 30-40 ° C and then cooled to 0 ° C. The hydrochloride salt of the molecule BA2 (2.95 g, 3.8 mmol) is suspended in DMF (45 mL) and triethylamine (0.39 g, 3.8

147 mmol) is then added to this suspension and the mixture is slightly heated with stirring until complete dissolution. To the solution of co-polyamino acid at 0 ° C., / V-methylmorpholine (NMM, 7.6 g, 75 mmol) in DMF (14 mL) and ethyl chloroformate (ECF, 8.1 g, 75 mmol) are added. After 10 min at 0 ° C, the solution of BA2 molecule is added and the medium maintained at 30 ° C for 1 h. The reaction medium is poured dropwise onto 6 L of water containing NaCl at 15% by mass and HCl (pH 2), then left to stand overnight. The precipitate is collected by filtration, washed with sodium chloride solution at pH 2 (1 L) and dried under vacuum for about 1 h. The white solid obtained is taken up in water (600 ml) and the pH is adjusted to 7 by slow addition of a 1N aqueous NaOH solution. The volume is adjusted to 700 ml by addition of water. After filtration through a 0.45 μm filter, the clear solution obtained is 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. After unloading, the solution is filtered through a 0.2 μm filter and stored at 2-8 ° C.

Dry extract: 19.7 mg / g

DP (estimated by NMR ^X H): 23

According to the NMR: i = 0.05

The calculated average molar mass of the co-polyamino acid BB1 is 4350 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2400 g / mol.

Example BB2: co-polyamino acid BB2 - sodium poly-L-glutamate modified by the molecule BA2 and having a number-average molar mase (Mn) of 4900 g / mol [000537] A poly-L-glutamic acid of average molar mass in number (Mn) 4100 g / mol (5.0 g) obtained by a process similar to that used for the preparation of the co-polyamino acid BB1-1 is dissolved in DMF (205 mL) at 30-40 ° C and then maintained at this temperature. In parallel, the hydrochloride salt of the BA2 molecule (1.44 g, 1.84 mmol) is suspended in DMF (10 mL) and triethylamine (0.19 g, 1.84 mmol) is added , then the mixture is slightly heated with stirring until complete dissolution. To the solution of co-polyamino acid in DMF, NMM (3.7 g, 36.7 mmol), the solution of molecule BA2 then of 2-hydroxypyridine / V-oxide (HOPO, 0.31 g, 2, 76 mmol) are added successively. The environment reacts! is then cooled to 0 ° C, then EDC (0.53 g, 2.76 mmol) is added and the medium is brought up to ambient temperature for 3 h. The reaction medium is poured

148 drop by drop on 1.55 L of water containing NaCl at 15% by mass and HCl (pH 2) with stirring. At the end of the addition, the pH is readjusted to 2 with a 1N HCl solution, and the suspension is left to stand overnight. The precipitate is collected by filtration, then rinsed with 100 ml of water. The white solid obtained is dissolved in 200 ml of water by slow addition of a 1N aqueous NaOH solution to pH 7 with stirring, then the solution is filtered through a 0.45 μm filter. The clear solution obtained is 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 solution obtained is filtered through a 0.2 μm filter and stored at 2-8 ° C.

Dry extract: 16.3 mg / g

DP (estimated by NMR ^X H): 21

According to the NMR ^X H: i = 0.047

The calculated average molar mass of the co-polyamino acid BB2 is 3932 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4900 g / mol.

Example BB3: Co-polyamino acid BB3 - sodium poly-L-glutamate modified by the molecule BA2 and having a number-average molar mass (Mn) of @ 400 g / mol

Co-polyamino acid BB3-1: poly-L-glutamic acid of number-average molar mass (Mn) 17,500 g / mol resulting from the polymerization of y-methyl-L-glutamate / V-carboxyanhydride initiated by L-leucinamide [000538 ] A poly-L-glutamic acid of number average mass (Mn) 17500 g / mol relative to a polymethyl methacrylate (PMMA) standard is obtained by polymerization of γ-methyl / V-carboxyanhydride of glutamic acid using Lleucinamide as initiator and by deprotecting the methyl esters by using a 37% hydrochloric acid solution according to the process described in patent application FR-A-2 801 226.

By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA2 (3.23 g, 4.1 mmol) and to the co-polyamino acid BB3-1 (11 g), a poly -Sodium glutamate modified by the BA2 molecule is obtained.

Dry extract: 27.5 mg / g

149

DP (estimated by NMR ^X H): 34

According to the NMR ^X H: li = 0.049

The calculated average molar mass of the co-polyamino acid BB3 is 6405 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 6400 g / mol.

Example BB4: co-polyamino acid BB4 - sodium poly-L-glutamate modified by the molecule BA2 and having a number-average molar mass (Mn) of 10500 g / mol [000540] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA2 (5 g, 6.35 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn ~ 10,800 g / mol (21.7 g) obtained by a process similar to that used for the preparation of co-polyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BA2 is obtained.

Dry extract: 28.2 mg / g

DP (estimated by NMR ^X H): 65

According to the NMR ^X H: i = 0.04

The calculated average molar mass of the co-polyamino acid BB4 is 11,721 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 10,500 g / mol.

Example BB5: Co-polyamino acid BB5 - sodium poly-L-glutamate capped at one of its ends by an acety group and modified by the molecule BA2 and having a number-average molar mass (Mn) of 3600 g / mol

Co-polyamino acid BB5-1: poly-L-glutamic acid with Mn 3700 g / mol resulting from the polymerization of γ-benzyl-L-glutamate / V-carboxyanhydride initiated by hexylamine and capped at one of its ends by a group acetylene [000541] In a flask previously dried in an oven is placed under vacuum ybenzyl-L-glutamate / V-carboxyanhydride (100.0 g, 380 mmol) for 30 min and then anhydrous DMF (250 mL) is introduced. The mixture is then stirred under argon until complete dissolution, cooled to 4 ° C, then hexylamine (2.3 mL, 17 mmol) is introduced quickly. The mixture is stirred between 4 ° C and room temperature

150 for 2 days then precipitated in diisopropyl ether (3.4 L). The precipitate is recovered by filtration, washed twice with diisopropyl ether (225 ml) then dried to give a white solid which is dissolved in 450 ml of THF. To this solution are successively added / V, / V-diisopropylethylamine (DIPEA, 31 mL, 176 mmol) then acetic anhydride (17 mL, 176 mmol). After stirring overnight at room temperature, the solution is poured slowly into diisopropyl ether (3 L) over a period of 30 min and with stirring. After 1 h of stirring, the precipitate is filtered, washed twice with diisopropyl ether (200 ml) then dried under vacuum at 30 ° C to give a poly (y-benzyl-L-glutamic acid) capped at one of its ends by an acetyl group. To a solution of the capped co-polyamino acid (72 g) in trifluoroacetic acid (TFA, 335 mL) at 4 ° C is added dropwise a solution of hydrobromic acid (HBr) at 33% in the acetic acid (235 mL, 1.34 mol). The mixture is stirred at room temperature for 3 h 30, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (4 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed with a 1: 1 (v / v) mixture of diisopropyl ether and water (340 mL) then with water (340 mL). The solid obtained is then solubilized in water (1.5 L) by adjusting the pH to 7 by adding an aqueous sodium hydroxide solution 10 N and then an aqueous sodium hydroxide solution 1 N. After solubilization, the theoretical concentration is adjusted at 20 g / L theoretical by addition of water to obtain a final volume of 2.1 L. The solution is filtered on a 0.45 μm filter then purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated until a final volume of 1.8 L is obtained. The aqueous solution is then acidified by adding 37% hydrochloric acid solution until reaching a pH of 2. After 4 h stirring, the precipitate obtained is filtered, washed with water (330 mL) and then dried under vacuum at 30 ° C to give a poly-L-glutamic acid of number average molar mass (Mn) 3700 g / mol compared to a polyoxyethylene (PEG) standard.

Co-polyamino acid BB5 By a process similar to that used for the preparation of copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA2 (6.92 g, 8.8 mmol) and to co-polyamino acid BB5-1 (30, 0 g), a sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule BA2 is obtained.

Dry extract: 29.4 mg / g

DP (estimated from NMR ^): 23

151

According to NMR: i = 0.042

The calculated average molar mass of the co-polyamino acid BB5 is 4302 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3600 g / mol.

Example BB6: Co-polyamino acid BB6 - sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule BA2 and having a number-average molar mass (Mn) of 4100 g / mol [000544] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA2 (5.8 g, 7.4 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn - 3800 g / mol (25 g) obtained by a process similar to that used for the preparation of copolyamino acid BB5-1 using ammonia in place of hexylamine, a sodium poly-Lglutamate capped at one of its ends by a acetyl group and modified by the molecule BA2 is obtained.

Dry extract: 27.6 mg / g

DP (estimated by NMR ^X H): 24

According to the NMR ^X H: i = 0.04

The calculated average molar mass of the co-polyamino acid BB6 is 4387 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4100 g / mol.

Example BB7: Co-polyamino acid BB7 - sodium poly-L-glutamate modified by the molecule BA2 and having a number-average molar mass (Mn) of 4200 g / mol [000545] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA2 (7.07 g, 9.0 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn = 3600 g / mol (30.0 g) obtained by a process similar to that used for the preparation of the copolyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BA2 is obtained.

Dry extract: 28.3 mg / g

DP (estimated by NMR ^X H): 22

152

According to the NMR ^X H: i = 0.042

The calculated average molar mass of the co-polyamino acid BB7 is 4039 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4200 g / mol.

Example BB8: co-polyamino acid BB8 - sodium poly-L-glutamate modified by the molecule BA2 and having a number-average molar mass (Mn) of 5200 g / mol [000546] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA2 (0.85 g, 1.1 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn = 4100 g / mol (5.0 g) obtained by a process similar to that used for the preparation of the copolyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BA2 is obtained.

Dry extract: 28.6 mg / g

DP (estimated by NMR ^X H): 21

According to the NMR ^X H: i = 0.026

The calculated average molar mass of the co-polyamino acid BB8 is 3620 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn - 5200 g / mol.

Example BB9: co-polyamino acid BB9 - sodium poly-L-glutamate modified by the molecule BA3 and having a number-average molar mass (Mn) of 4700 g / mol [000547] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA3 (3.05 g, 3.6 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn = 4100 g / mol (10.0 g) obtained by a process similar to that used for the preparation of the copolyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BA3 is obtained.

Dry extract: 28.6 mg / g

DP (estimated by NMR ^X H): 26

153

According to the NMR ^X H: i = 0.05

The calculated average molar mass of the co-polyamino acid BB9 is 4982 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4700 g / mol.

Example BB1O: co-polyamino acid BB1O - sodium poly-L-glutamate modified by the molecule BA3 and having a number-average molar mass (Mn) of 4200 g / mol [000548] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA3 (1.90 g, 2.3 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn = 3500 g / mol (10.0 g) obtained by a process similar to that used for the preparation of the copolyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BA3 is obtained.

Dry extract: 25.9 mg / g

DP (estimated from ¹ H NMR): 22

According to the NMR ^X H: i = 0.029

The calculated average molar mass of the co-polyamino acid BB10 is 3872 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn - 4200 g / mol.

Example BB11: co-polyamino acid BB11 - sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule BA4 and having a number-average molar mass (Mn) of 3900 g / mol [000549] By a process similar to that used for the preparation of copolyamino acid BB2 applied to the hydrochloride salt of the molecule BA4 (2.21 g, 2.2 mmol) and to a poly-L-glutamic acid of average mass in number Mn - 3700 g / mol (10 g) obtained by a process similar to that used for the preparation of copolyamino acid BB5-1, a sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule BA4 is obtained.

Dry extract: 28.1 mg / g

DP (estimated by NMR ^X H): 22

154

According to the NMR ^X H: i = 0.032

The calculated average molar mass of the co-polyamino acid BB11 is 4118 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3900 g / mol.

Example BB12: co-polyamino acid BB12 - sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule BA3 and having a number-average molar mass (Mn) of 3900 g / mol [000550] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride salt of the BA3 molecule (1.9 g, 2.3 mmol) and to a poly-L-glutamic acid of average mass in number Mn = 3600 g / mol (10 g) obtained by a process similar to that used for the preparation of copolyamino acid BB5-1, a sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified by the molecule BA3 is obtained.

Dry extract: 26.7 mg / g

DP (estimated by NMR ^X H): 23

According to the NMR ^X H: i = 0.03

The calculated average molar mass of the co-polyamino acid BB12 is 4145 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3900 g / mol.

Example BB13: co-polyamino acid BB13 - sodium poly-L-glutamate modified by the BAI molecule and having a number-average molar mass (Mn) of 2800 g / mol [000551] By a process similar to that used for the preparation of the copolyamino acid BB1 applied to the hydrochloride salt of the BAI molecule (3.65 g, 5 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn = 3600 g / mol (10 g) obtained by a similar process to that used for the preparation of the co-polyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BAI is obtained.

Dry extract: 25.6 mg / g

DP (estimated by NMR ^X H): 25

155

According to the NMR ^X H: i = 0.08

The calculated average molar mass of the co-polyamino acid BB13 is 5253 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2800 g / mol.

Example BB14: co-polyamino acid BB14 - sodium poly-L-glutamate modified at one of its ends by the molecule BA2 and having a number-average molar mass (Mn) of 4020 g / mol [000552] A suitable container is introduced successively the hydrochloride salt of the BA2 molecule (2.12 g, 2.70 mmol), chloroform (40 mL), 4 A molecular sieve (1.5 g), as well as Amberlite ion exchange resin IRN 150 (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 balloon previously dried in an oven, γ-benzyl-L-glutamate Ncarboxyanhydride (18 g, 68.42 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 BA2 molecule prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to room temperature then poured dropwise into diisopropyl ether (1.2 L) with stirring. The white precipitate is recovered by filtration, washed twice with diisopropyl ether (100 ml) then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (105 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (38 mL, 220 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (600 mL). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with a 1: 1 mixture (v / v) of diisopropyl ether and water (200 ml) then with water (100 ml). The solid obtained is dissolved in water (450 mL) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. The mixture is filtered on a 0.45 μm filter. then is purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution

156 is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7.0. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 22.3 mg / g

DP (estimated by NMR ^X H) - 29 thus i = 0.034

The calculated average molar mass of the co-polyamino acid BB14 is 5089 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4020 g / mol.

Example BB15: co-polyamino acid BB15 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 3389 g / mol [000554] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA3 (3.62 g, 4.32 mmol) and to 25.0 g (94.97 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride , a sodium polyL-glutamate modified at one of its ends by the molecule BA3 is obtained.

Dry extract: 30.4 mg / g

DP (estimated by NMR ^X 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 = 3389 g / mol.

Example BB16: co-polyamino acid BB16 - sodium poly-L-glutamate modified at one of its ends by the molecule BA4 and having a number-average molar mass (Mn) of 3300 g / mol [000555] By a process similar to that used for the preparation of BB14 copolyamino acid applied to se! hydrochloride of the BA4 molecule (5.70 g, 5.70 mmol) and 29.99 g (113.9 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a modified sodium poly-L-glutamate at one of its ends by the BA4 molecule is obtained.

Dry extract: 32.3 mg / g

DP (estimated by NMR ^X H) - 23 i so - 0.043

The calculated average molar mass of the co-polyamino acid BB16 is 4399 g / mol.

157

Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / mol.

Example BB17: co-polyamino acid BB17 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass of 10700 g / mol [000556] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA3 (2.51 g, 3 mmol) and to 52.7 g (200 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a sodium poly-Lglutamate modified at one of its ends by the BA3 molecule is obtained.

Dry extract: 24.5 mg / g

DP (estimated by NMR ^X H) = 65 therefore i = 0.015

The calculated average molar mass of the co-polyamino acid BB17 is 10585 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn - 10700 g / mol.

Example BB1S: co-polyamino acid BB1S - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass of 6600 g / mol [000557] By a process similar to that used for the preparation of copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA3 (2.51 g, 3 mmol) and to 31.6 g (120 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a sodium poly-Lglutamate modified at one of its ends by the BA3 molecule is obtained.

Dry extract: 27.3 mg / g

DP (estimated by NMR ^X H) = 40 therefore i = 0.025

The calculated average molar mass of the co-polyamino acid BB18 is 6889 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 6600 g / mol.

Example BB19: Co-polyamino acid BB19 - sodium poly-L-glutamate and modified by the molecule BA3 and having a number-average molar mass (Mn) of 7700 g / mol [000558] By a process similar to that used for the preparation copolyamino acid AB23 applied to the hydrochloride salt of the BA3 molecule and to the co

158 polyamino acid AB23-1, a sodium poly-L-glutamate modified by the molecule BA3 is obtained.

Dry extract: 25.3 mg / g

DP (estimated by NMR ^X H): 60

According to the NMR ^X H: i = 0.045

The calculated average molar mass of the co-polyamino acid BB19 is 11188 g / mol.

Organic HPLC-SEC (PEG calibrator): Mn = 7700 g / mol.

Example BB20: co-polyamino acid BB2O - sodium poly-L-glutamate modified at one of its ends by the BAS molecule and having a number-average molar mass (Mn) of 2800 g / mol [000559] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the BA5 molecule in the form of free amine (1.70 g, 1.98 mmol) and γ-benzyl-L-glutamate / V-carboxyanhydride (11.46 g, 43, 5 mmol), a sodium polyL-glutamate modified at one of its ends by the molecule BAS is obtained.

Dry extract: 20.7 mg / g

DP (estimated by NMR ^X H) = 23 therefore i = 0.043

The calculated average molar mass of the co-polyamino acid BB20 is 4295 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2800 g / mol.

Example BB21: co-polyamino acid BB21 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 1100 g / mol [000560] By a process similar to that used for the preparation of copolyamino acid BB14 applied to the BA3 molecule in the form of free amine (3.814 g, 4.75 mmol) and γ-benzyl-L-glutamate / V-carboxyanhydride (10.0 g, 38.0 mmol ), a sodium poly-L-glutamate modified at one of its ends by the molecule BA3 is obtained.

Dry extract: 16.1 mg / g

DP (estimated by NMR ^X H) = 9 therefore i = 0.11

159

The calculated average molar mass of the co-polyamino acid BB21 is 2123 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 1100 g / mol.

Example BB22: co-polyamino acid BB22 - sodium poly-L-glutamate modified at one of its ends by the molecule BA6 and having a number-average molar mass (Mn) of 3300 g / mol [000561] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the BA6 molecule in the form of free amine (4.45 g, 5.18 mmol) and to 30.0 g (113.96 mmol) of y-benzyl-L-glutamate / V-carboxyanhydride, a sodium poly-L-glutamate modified at one of its ends by the molecule BA6 is obtained.

Dry extract: 29.0 mg / g

DP (estimated by NMR * H) = 25 therefore i = 0.04

The calculated average molar mass of the co-polyamino acid BB22 is 4597 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / mol.

Example BB23: co-polyamino acid BB23 - sodium poly-L-glutamate modified at one of its ends by the molecule BA7 and having a number-average molar mass (Mn) of 2900 g / mol [000562] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the molecule BA7 in the form of free amine (3.05 g, 4.01 mmol) and of γ-benzyl-L-glutamate / V-carboxyanhydride (22.78 g, 86, 5 mmol), a sodium polyL-glutamate modified at one of its ends by the molecule BA7 is obtained.

Dry extract: 16.9 mg / g

DP (estimated by NMR ^Χ Η) = 21 therefore i = 0.048

The calculated average molar mass of the co-polyamino acid BB23 is 3894 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2900 g / mol.

160

Example BB24: co-polyamino acid BB27 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and modified by the molecule BA3 and having a number-average molar mass (Mn) of 2300 g / mol [ 000563] Co-polyamino acid BB24-1: poly-L-glutamic acid modified at one of its ends by the molecule BA3 and capped at the other end by pidolic acid.

In a flask previously dried in an oven, y-benzyl-L-glutamate / V-carboxyanhydride (122.58 g, 466 mmol) is placed under vacuum for 30 min and then anhydrous DMF (220 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to -10 ° C, then a solution of BA3 molecule in the form of free amine (17.08 g, 21.3 mmol) in chloroform (40 mL) is introduced quickly. The mixture is stirred between 0 ° C and room temperature for 2 days, then heated to 65 ° C for 4 h. The reaction mixture is then cooled to 25 ° C and then added pidolic acid (13.65 g, 105.8 mmol), HOBt (2.35 g, 15.3 mmol) and EDC (20 , 28 g, 105.8 mmol). After 24 h of stirring at 25 ° C., the solution is concentrated under vacuum to remove the chloroform and 50% of the DMF. The reaction mixture is then heated to 55 ° C. and 1150 ml of methanol are introduced over 1 hour. The reaction mixture is then cooled to 0 ° C. After 18 h, the white precipitate is recovered by filtration, washed three times with 270 ml of diisopropyl ether and then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (390 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (271 mL, 1547 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (970 mL). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with diisopropyl ether (380 ml) then twice with water (380 ml). The solid obtained is dissolved in water (3.6 L) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. The mixture is filtered on filter 0, 45 μm then is purified by ultrafiltration against a 0.9% NaCl solution, a 0.1 N NaOH solution, a 0.9% NaCl solution, a phosphate buffer solution (150 mM), a NaCl solution 0 , 9% then water until the conductivity of the permeate is less than 50 pS / cm. The copolyamino acid solution is then concentrated to approximately 30 g / L theoretical, filtered through 0.2 μm and then acidified to pH 2 with stirring by addition of a 37% HCl solution. The precipitate is then recovered by filtration, washed twice with water and then dried under vacuum at 30 ° C to obtain a white solid.

161

Co-polyamino acid BB24 By a process similar to that used for the preparation of copolyamino acid BB2 applied to the BA3 molecule in the form of free amine (1.206 g, 1.50 mmol) and to co-polyamino acid BB24-1 (5 , 5 g, 33.4 mmol), a sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and modified by the molecule BA3 is obtained.

Dry extract: 19.0 mg / g

DP (estimated by NMR ^X H): 22

According to the NMR ^X H: i = 0.089

The calculated average molar mass of the co-polyamino acid BB24 is 4826 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2300 g / mol.

Example BB25: co-polyamino acid BB25 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and at the other end by the molecule B8 and having a number-average molar mass (Mn) of 2000 g / mol [000566] To a solution of molecule B8 (0.946 g, 1.24 mmol) in DMF (8 mL) are introduced DCC (0.257 g, 1.24 mmol) and NHS (0.143 g, 1.24 mmol ). After 16 h of stirring at room temperature, the solution is filtered to be used directly in the following reaction.

In a flask previously dried in an oven, y-benzyl-L-glutamate / V-carboxyanhydride (6.0 g, 22.8 mmol) is placed under vacuum for 30 min and then anhydrous DMF (14 mL ) is introduced. The mixture is then stirred under argon until complete dissolution, cooled to 0 ° C., then a solution of BA3 molecule in the form of free amine (0.832 g, 1.04 mmol) in chloroform (2.0 ml) is introduced quickly. After 18 h of stirring at 0 ° C., the solution of molecule B8 prepared previously is added. The solution is stirred between 0 ° C and room temperature for 22 h then poured dropwise into diisopropyl ether (0.34 L) with stirring. The precipitate is recovered by filtration, washed with diisopropyl ether (7 times 15 mL) then dried under vacuum at 0 ° CA30 ° C to give a white solid. The solid is diluted in TFA (23 mL), then the solution is cooled to 4 ° C. A 33% HBr solution in acetic acid (15 mL, 85.7 mmol) is then added dropwise. The mixture is stirred at room temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (0.28 L). After 2 h

With stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed twice with a 1: 1 (v / v) mixture of diisopropyl ether and water (24 mL) then twice with water (24 mL). The solid obtained is then dissolved in water (0.16 L) by adjusting the pH to 12 by adding an aqueous solution of sodium hydroxide 10 N then an aqueous solution of sodium hydroxide 1 N. After 30 min the pH is adjusted to 7 by slow addition of a 1N aqueous HCl solution. The solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductivity of the permeate is less than 50 pS / cm. The solution obtained is filtered through a 0.2 μm filter and stored at 2-8 ° C.

Dry extract: 18.9 mg / g

DP (estimated by NMR ^X H): 22

According to the NMR ^X H: ii = 0.09

The calculated average molar mass of the co-polyamino acid BB25 is 4871 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 2000 g / mol.

163

B. COMPOSITIONS

Example BV1: Preparation of a 0.6 mg / ml human amylin solution containing m-cresol (29 mM), glycerin (174 mM) at pH 7.4.

A concentrated human amylin solution at 3 mg / ml is prepared by dissolving human amylin in the form of a powder purchased from AmbioPharm. This solution is added to a concentrated solution of excipients (m-cresol, glycerin) so as to obtain the intended final composition. The final pH is adjusted to 7.4 by adding NaOH / HCl.

Example BV2: Preparation of a 0.6 mg / mL human amylin solution containing co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 7.4.

[000569] A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin) to a concentrated solution of co-polyamino acid BB15.

The concentrated human amylin solution at 3 mg / MI BV1 is added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to obtain the final compositions BV5 to BV11 (table lg). The final pH is adjusted to 7.4 by adding NaOH / HCl.

Solution Ratio BB15 / human amylin BB15 copolyamino acid concentration Visual aspect of the solution mol / mol mg / mL mM BV1 - limpid BV5 5 3 0.73 limpid BV6 6 3.6 0.88 limpid BV7 7 4.2 1.03 limpid BV8 8  4.8 1.17 limpid BV9 9 5.4 1.32 limpid BV10 10 6 1.47 limpid BV11 17 10.5 2.57 limpid

Table lg: Compositions and visual appearance of solutions of human amylin at pH 7.4 at different concentrations of co-polyamino acid BB15.

Example BY1: Preparation of a 0.9 mg / mL pramlintide solution containing m-cresol (29 mM) and glycerin (174 mM) at pH 7.4.

A concentrated pramlintide solution at 5 mg / mL is prepared by dissolving pramlintide in the form of a powder purchased from Hybio. This solution is

164 added to a concentrated solution of excipients (m-cresol, glycerin) so as to obtain the intended final composition. The final pH is adjusted to 7.4 by adding NaOH / HCl.

Example BW1: Preparation of a 0.4 mg / ml pramlintide solution containing phenol (30 mM), glycerin (174 mM) and glycylglycine (S mM) at pH 7.4.

By a process similar to that used in Example BY1, a 0.4 mg / mL pramlintide solution containing phenol (30 mM), glycerin (174 mM) and glycylglycine (8 mM) at pH 7.4 is obtained.

Example BYO: Preparation of a 0.9 mg / ml pramlintide solution containing co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 7.4.

[000573] A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin) to a concentrated solution of co-polyamino acid BB15.

A concentrated pramlintide solution at 5 mg / ml is added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to obtain the final compositions BY2 to BY8 (Table 3). The final pH is adjusted to 7.4 by adding NaOH / HCl.

Solution Ratio BB15 / pramlintide BB15 copolyamino acid concentration Visual aspect of the solution mol / mol mg / mL mM BY1 - - limpid BY2 2 1.8 0.44 limpid BY3 3 2.7 -. .0, .66. limpid BY4 4 3.6 0.88 limpid BY5 5 4.5 1.10 limpid by6 6 5.4 1.32 limpid BY7 10 9 2.20 limpid

Table 3: Compositions and visual appearance of pramlintide solutions at pH 7.4 at different concentrations of co-polyamino acid BB15.

Example BW0: Preparation of a 0.4 mg / mL pramlintide solution containing co-polyamino acid BB15, phenol (30 mM), ia glycerin (174 mM) and ia glycylglycine (8 mM) at pH 7, 4.

By a protocol similar to that used in the example BYO, from a pramlintide solution at 0.4 mg / mL BW1, pramlintide solutions at 0.4 mg / mL containing co-polyamino acid BB15 , phenol (30 mM), glycerin (174 mM) and glycylglycine (8 mM) at pH 7.4 BW2 and BW3 are obtained.

165

Solution BB15 copolyamino acid concentration BB15 / pramlintide ratio Visual aspect of the solution mg / ml mM mol / mol BW2 2X 0.59 6 limpid BW3 4 0.98 10 limpid

Table 4: Compositions and visual appearance of solutions of pramlintide at 0.4 mg / ml at pH 7.4 at different concentrations of co-polyamino acid BB15.

Example BPO: Preparation of a pramlintide solution at 0.9 mg / ml containing various co-polyamino acids of the invention, m-cresol (29 mM) and glycerin (174 mM) at pH 7.4.

By a protocol similar to that described in Example BYO, solutions of pramlintide at 0.9 mg / ml containing different co-polyamino acids of the invention, mresol (29 mM) and glycerin (174 mM ) at pH 7.4 BP2 to BP12 are obtained.

Solu tion Copolya mino acid Concentration in copolyamino acid Ratio copolyamino acid / p ramlintide Visual aspect of the solution mg / m The mM mol / mol BP2 BB15 5 10 1.22 2.45 5.4 10.8 limpid limpid BP3 BB14 5 10 0.98 1.96 4.3 8.6 limpid limpid BP4 AB17 5 10 1.11 1.22 4.9 9.8 limpid limpid BPS AB15 5 10 0.99 1.99 4.4 8.8 ................................. limpid limpid BP6 AB14 5 10 1.48 2.96 6.5 13 limpid limpid BP10 BB18 5 10 0.72 1.44 3.2 6.3 limpid limpid BP11 BB9 5 10 1 2.01 4.4 8.8 limpid limpid BP12 BB2 5 10 1.27 2.54 5.6 ........................ limpid limpid

Table 8: Compositions and visual appearance of solutions of pramlintide at 0.9 mg / ml at pH

7.4 in the presence of different co-polyamino acids.

166

Example BH1: Preparation of a 0.6 mg / mL pramlintide solution containing m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 [000577] A concentrated pramlintide solution at 5 mg / mL is prepared by dissolving pramlintide in the form of a powder purchased from Ambiopharm. This solution is added to a concentrated solution of excipients (m-cresol, glycerin) so as to obtain the intended final composition. The final pH is adjusted to 6.6 by adding NaOH / HCl.

Example BHO: Preparation of a 0.6 mg / ml pramlintide solution containing co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 [000578] A solution concentrated BB15 co-polyamino acid and excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin) to a concentrated solution of co-polyamino acid BB15.

A concentrated pramlintide solution at 5 mg / ml at pH 4 is added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to obtain the final compositions BH2 to BH8 (Table 9). The final pH is adjusted to 6.6 by adding NaOH / HCl.

Solution BB15 / pramlintide ratio BB15 copolyamino acid concentration Visual aspect of the solution mol / mol mg / mL mM BH1 - - limpid BH2 2 1.3 0.29 limpid BH3 3 2 0.45 limpid BH4 4 2.7 0.61 limpid BH5 6 4 0.90 limpid BH6 8 5.3 1.19 limpid BH7 10 6.7 1.50 limpid BH8 15 10 2.24 limpid

Table 9: Compositions and visual appearance of pramlintide solutions at pH 6.6 at different concentrations of co-polyamino acid BB15.

BIO Example: Preparation of a 0.6 mg / mL pramlintide solution containing various co-polyamino acids of the invention, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6

167 [000580] By a protocol similar to that described in Example BHO, solutions of pramlintide at 0.6 mg / ml containing different co-polyamino acids of the invention, mresol (29 mM) and glycerin (174 mM) at pH 6.6 CA3-1 to CA3-14 are obtained.

Solutio n Copolyaminoacid e Concentration in copolyamino acid Ratio co- polyamino / pramlintid e Visual aspect of the solution mg / m The mM mol / mol BII BB20 1.3 0.3 2 limpid 2.6 0.6 4 limpid BI2 BB21 1.3 0.6 4 limpid BI 3 AB22 2.4 0.3 2 limpid BI4 BB24 2.9 0.6 4 limpid BIS BB25 1.5 0.3 2 limpid 3 0.6 4 limpid BI6 AB23 3.4 0.23 2 limpid BI7 AB28 2.3 0.3 2 limpid 4.7 0.6 4 limpid BI8 AB24 1.2 0.15 1 limpid 2.4 0.3 2 limpid BI9 AB25 1.3 0.15 1 limpid 2.6 0.3 2 limpid BI10 AB26 0.7 0.15 1 limpid 1.5 0.3 2 limpid Bill AB27 1.3 0.15 1 limpid 2.7 0.3 2 limpid BI12 AB31 1.3 0.15 1 limpid 2.5 0.3 2 limpid BI13 AB29 8.9 1.15 7.6 limpid BI14 AB32 1.3 0.15 1 limpid 2.5 0.3 2 limpid

Table 10: Compositions and visual appearance of pramlintide solutions at pH 6.6 in the presence of different co-polyamino acids.

168

Example BTO: Preparation of a 0.6 mg / mL pramlintide solution containing AB14 co-polyamino acid, m-cresol (29 mM), glycerin (174 mM) NaCl and zinc chloride at pH 6 , 6 [000581] A concentrated solution of co-polyamino acid AB14 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, NaCl, zinc chloride) to a concentrated solution of co-polyamino acid AB14.

A concentrated pramlintide solution at 5 mg / ml at pH 4 is added to this concentrated solution of co-polyamino acid AB14 and of excipients so as to obtain the final compositions BT1 to BT5 (Table 11). The final pH is adjusted to 6.6 by adding NaOH / HCl.

Solution Co- polyamino Concentration in co-polyamino acid [NaCl] [ZnCI ₂ ] Aspect visual of the solution mg / mL mM (MM) (MM) limpid BT1 AB14 6.3 1.87 0.75 limpid BT2 AB14 6.3 1.87 50 limpid BT3 AB14 6.3 1.87 100 limpid BT4 AB14 6.3 1.87 50 0.75 limpid BT5 AB14 6.3 1.87 100 0.75 limpid

Table 11: Compositions and visual appearance of pramlintide solutions at pH 6.6 in the presence of co-polyamnioacid AB14 and of different contents of sodium chloride and zinc chloride.

BSO Example: Preparation of a 0.6 mg / mL pramlintide solution containing various co-polyamino acids of the invention, m-cresol (29 mM), glycerin (174 mM), NaCl and zinc chloride at pH 6.6 [000583] By a protocol similar to that described in Example CA4, solutions of pramlintide at 0.6 mg / ml containing different co-polyamino acids of the invention, mresol (29 mM) and glycerin (174 mM), sodium chloride and zinc chloride at pH 6.6 BS1 to BS11 are obtained.

169

Solution Co- polyamino Concentration in copolyamino [NaCl] [ZnCI ₂ ] Aspect visual of the solution mg / mL mM (MM) (MM) BS1 AB15 7.8 1.6 limpid BS2 AB15 11.7 2.3 i. ":; limpid BS3 AB15 3.9 0.8 50 limpid BS4 AB15 6.3 1.3 50 <· * ^? ..... limpid BS5 AB15 7.8 1.6 50 limpid BS6 AB15 3.9 0.8 100 limpid BS7 AB16 12.4 1.5 i limpid BS8 AB16 16.7 2.1 limpid BS9 AB16 7.4 0.9 50 limpid BS10 AB16 12.4 1.5 50 limpid BS11 AB16 7.4 0.9 50 1 limpid

Table 12: Compositions and visual appearance of pramlintide solutions at pH 6.5 in the presence of different co-polyamino acids and different contents of sodium chloride and zinc chloride

170

Example BX1: Preparation of a solution of human amylin at 0.6 mg / ml and of human insulin at 100 IU / ml containing m-cresol (29 mM), glycerin (174 mM) and chloride zinc (229 pM) at pH 7.4.

The concentrated human amylin solution at 3 mg / mL BV1 is added to a concentrated solution of excipients (m-cresol, glycerin). A 500 IU / mL human insulin solution is prepared by dissolving human insulin in the form of a powder purchased from Amphastar. This solution is added to the concentrated solution of human amylin and of excipients so as to obtain the intended final composition. The final pH is adjusted to 7.4 by adding NaOH / HCl.

Example BX2: Preparation of a 0.6 mg / mL human amylin solution and 100 IU / mL human insulin containing co-polyamino acid BB15, mresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH

7.4.

[000585] A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, zinc chloride) to a concentrated solution of co-polyamino acid BB15.

A concentrated human amylin solution at 3 mg / ml and then a human insulin solution at 500 IU / ml are added to the concentrated solution of copolyamino acid BB15 and of excipients so as to obtain the final composition targeted (table 13). The final pH is adjusted to 7.4 by adding NaOH / HCl.

The BX1, BX6, BX10 and BX11 solutions are prepared according to the above protocol.

Solution BB15 / human amylin ratio BB15 copolyamino acid concentration Visual aspect of the solution mol / mol mg / MI mM BX1 turbid BX6 6 3.6 0.88 limpid BX10 10 6 1.47 limpid BX11 17 10.5 2.57 limpid

Table 13: Compositions and visual appearance of solutions of human amylin and human insulin at pH 7.4 at different concentrations of co-polyamino acid BB15.

In the presence of the co-polyamino acid BB15, a clear solution of human amylin (0.6 mg / ml) and human insulin (100 IU / ml) is obtained at pH 7.4.

171

Example BN1: Preparation of a 0.4 mg / ml pramlintide solution and 100 IU / ml human insulin containing phenol (30 mM), glycerin (174 mM), glycylglycine (S mM) and zinc chloride (229 pM) at pH 7.4. A concentrated pramlintide solution at 5 mg / ml is added to a concentrated solution of excipients (m-cresol, glycerin, glycylglycine, zinc chloride). A solution of human insulin at 500 IU / mL is added to this concentrated solution of pramlintide and of excipients so as to obtain the final composition targeted. The final pH is adjusted to 7.4 by adding NaOH / HCl.

Example BRI: Preparation of a solution of pramlintide at 0.9 mg / mL and human insulin at 100 IU / mL containing m-cresol (29 mM), glycerin (174 mM) and zinc chloride ( 229 pM) at pH 7.4.

By a process similar to that used in Example BN1, a solution of pramlintide at 0.9 mg / mL and human insulin at 100 IU / mL containing m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 7.4 is obtained.

Example ΒΝ0: Preparation of a pramlintide solution at 0.4 mg / mL and human insulin at 100 IU / mL containing co-polyamino acid BB15, phenol (30 mM), glycerin (174 mM), glycylglycine (8 mM) and zinc chloride (229 pM) at pH 7.4.

A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, glycylglycine, zinc chloride) to a concentrated solution of co-polyamino acid BB15. A concentrated pramlintide solution at 5 mg / mL and then a solution of human insulin at 500 IU / mL are added to this concentrated solution of copolyamino acid BB15 and of excipients so as to obtain the final composition targeted (Table 14) . The final pH is adjusted to 7.4 by adding NaOH / HCl.

The BN2 and BN3 solutions are prepared according to the above protocol.

172

Solution Concentration in copolyamino acid BB15 Ratio BB15 / pramlintide Visual appearance of the mixture mg / mL mM mol / mol BN1 X: ' turbid BN2 2.4 0.59 6 limpid BN3 4 0.98 10 limpid

Table 14: Compositions and visual appearance of the solutions of pramlintide at 0.4 mg / ml and human insulin at 100 IU / ml at pH 7.4 at different concentrations of copolyamino acid BB15.

In the presence of co-polyamino acid BB15, a clear solution of pramlintide (0.4 mg / ml) and human insulin (100 IU / ml) is obtained at pH 7.4.

Example BRO: Preparation of a 0.9 mg / ml pramlintide solution and 100 IU / ml human insulin containing co-polyamino acid BB15, mresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH

7.4.

By a process similar to that used in the BNO example, a solution of pramlintide at 0.9 mg / ml_ and human insulin at 100 IU / ml containing copolyamino acid BB15, m-cresol (29 mM) , glycerin (174 mM) and zinc chloride (229 μΜ) at pH 7.4 is obtained.

The solutions BR2 to BR4 and BU2 to BU8 are prepared according to the above protocol.

Solution BB15 copolyamino acid concentration Ratio BB15 / pramlintide mol / mol Visual aspect of the solution mg / mL mM BIS .. - turbid BR2 2.7 0.66 3 limpid BR3 3.6 0.88 4 limpid BR4 4.5 1.10 5 limpid BU2 0.9 0.22 1 limpid BU3 1.8 0.44 2 limpid BU7 5.4 1.32 6 limpid BUS 9 2.20 10 limpid

Table 15: Compositions and appearance of the solutions of pramlintide at 0.9 mg / ml and human insulin at 100 IU / ml at pH 7.4 at different concentrations of copolyamino acid BB15.

173 [000597] In the presence of co-polyamino acid BB15, a clear solution of pramlintide (0.9 mg / ml) and human insulin (100 IU / ml) at pH 7.4 is obtained.

Example BGO: Preparation of a pramlintide solution at 0.9 mg / mL and human insulin at 100 IU / mL containing various co-polyamino acids of the invention, m-cresol (29 mM), glycerin ( 174 mM) and zinc chloride (229 μΜ) at pH 7.4.

By a process similar to the BNO example, a solution of pramlintide at 0.9 mg / mL and human insulin at 100 IU / mL containing a co-polyamino acid of the invention, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 7.4 is obtained.

The BG2 to BG12 solutions are prepared according to the protocol described above.

Solutio n Copolyaminoaci of Concentration in copolyaminoaci of Ratio Co- polyamino acid / pramlint ide Visual aspect of the solution mg / m The mM me / mol BG2 BB15 5 10 1.22 2.45 5.4 10.8 limpid limpid BG3 BB14 5 10 0.98 1.96 4.3 8.6 limpid BG4 AB17 5 10 1.11 1.22 4.9 9.8 limpid limpid BG5 AB15 5 10 0.99 1.99 4.4 8.8 limpid BG6 AB14 5 10 1.48 2.96 6.5 13 limpid BG10 BB18 5 10 0.72 1.44 3.2 6.3 limpid limpid BG11 BB9 5 10 1 2.01 4.4 8.8 limpid limpid BG12 BB2 5 10 1.27 2.54 5.6 11.2 limpid limpid

Table 16: Compositions and visual appearance of solutions of pramlintide at 0.9 mg / ml and human insulin at 100 IU / ml at pH 7.4 at different concentrations of co polyamino acids.

174

Example BD1: Preparation of a pramlintide solution at 0.9 mg / mL and insulin lispro at 100 IU / mL containing m-cresol (29 mM), glycerin (174 mM) and zinc chloride ( 300 μΜ) at pH 7.4.

A concentrated pramlintide solution at 5 mg / mL is added to a concentrated solution of excipients (m-cresol, glycerin, zinc chloride). A solution of insulin lispro at 500 IU / mL is added to this concentrated solution of pramlintide and of excipients so as to obtain the final composition targeted. The final pH is adjusted to 7.4 by adding NaOH / HCl.

BDO example: Preparation of a pramlintide solution at 0.9 mg / mL and insulin lispro at 100 IU / mL containing co-polyamino acid BB15, mresol (29 mM), glycerin (174 mM) and zinc chloride (300 pM) at pH

7.4.

[000601] A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, zinc chloride) to a concentrated solution of co-polyamino acid BB15.

A concentrated solution of pramlintide at 5 mg / ml and then a solution of insulin lispro at 500 IU / ml are added to the concentrated solution of copolyamino acid BB15 and of excipients so as to obtain the intended final composition. The final pH is adjusted to pH 7.4 by adding NaOH / HCl.

BD3 to BD9 solutions are prepared according to the protocol described above.

Solution Ratio BB15 / pramlintide Co-polyamino acid BB15 concentration Visual aspect of the solution mol / mol mg / ml mM BD1 - • - - turbid BD3 2 1.8 0.44 limpid BD4 3 2.7 0.66 limpid BD5 4 3.6 0.88 limpid BD6 5 4.5 1.10 limpid BD7 6 5.4 1.32 limpid BD8 10 9 2.20 limpid BD9 15 13.5 3.30 limpid

Table 17: Compositions and visual appearance of the solutions of pramlintide at 0.9 mg / ml and insulin lispro at 100 IU / ml at pH 7.4 at different concentrations of co-polyamino acid BB15.

In the presence of co-polyamino acid BB15, a clear solution of pramlintide (0.9 mg / ml) and insulin lispro (100 IU / ml) at pH 7.4 is obtained.

175

Example BK1: Preparation of a 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin containing m-cresol (29 mM), glycerin (174 mM) and zinc chloride ( 229 μM) at pH 6.6 [000605] By a process similar to that used in Example BRI, a solution of pramlintide at 0.6 mg / ml and human insulin at 100 IU / ml containing m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6 is obtained. [000606]

Example BKO: Preparation of a 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin containing co-polyamino acid BB15, mresol (29 mM), glycerin (174 mM) and zinc chloride (229 pM) at pH 6.6 [000607] By a process similar to that used in Example BR0, a solution of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL containing copolyamino acid BB15, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6 is obtained.

The solutions BK2 to BK8 are prepared according to the above protocol.

Solution BB15 / pramlintide ratio BB15 copolyamino acid concentration Visual aspect of the solution mol / mol mg / mL mM BK1 ; - - turbid BK2 2 1.3 0.29 limpid BK3 3 2 0.45 limpid BK4 4 2.7 0.61 limpid BK5 6 4 0.90 limpid BK6 8 5.3 1.19 limpid BK7 10 6.7 1.50 limpid BK8 15 10 2.24 limpid

Table 18: Compositions and visual appearance of the solutions of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL pH 6.6 at different concentrations of copolyamino acid BB15.

[000609] In the presence of co-polyamino acid BB15, a clear solution of pramlintide (0.6 mg / mL) and human insulin (100 IU / mL) at pH 6.6 is obtained.

Example BMO: Preparation of a solution of pramlintide at 0.6 mg / ml and human insulin at 100 IU / ml at pH 6.6 containing various copolyamino acids of the invention, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 pM) at pH 6.6 [000610] By a process similar to example BG0, solutions of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL containing different co-polyamino acids of the invention, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6 are obtained.

176 [000611] The BMI to BM18 solutions are prepared according to the protocol described above.

Solutio r: Copolyaminoacid e Concentration in copolyamino acid Ratio co- polyamino / pramlintid e Visual aspect of the solution mg / m L mM mol / mol BMI BB20 2.6 5.3 0.61 1.22 4 8 limpid limpid BM2 BB21 1.3 0.6 4 limpid BM3 AB22 2.4 0.3 2 limpid BM4 BB24 2.9 0.6 4 limpid BM5 BB23 3 0.76 5 Ί limpid 6MT BB25 1.5 0.3 2 limpid BM7 BB22 2.7. 4 limpid BM8 AB23 7.7 0.69 4.6 limpid BM9 BB19 4.7 0.4 2.8 limpid BM10 AB28 2.3 0.3 2 limpid BM11 AB24 1.2 ...... 7 0.15 . 0.3. .. 1 2 limpid limpid BM12 AB25 2.6 0.3 2 limpid BM13 AB26 1.5 2.3 0.3 0.5 2 3 limpid limpid BM14 AB27 1.3 2.7 0.15 0.3 1 2 limpid limpid BM15 AB30 1.2 2.3 0.15 0.3 1 2 limpid limpid BM16 AB31 1.3 ^ 5 0.15 0.3 1 2 limpid limpid BM17 AB29 5.9 8.9 0.8 1.15 5 7.6 limpid limpid BM18 AB32 2.5 0.3 2 limpid

Table 19: Compositions and visual appearance of the solutions of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL at pH 6.6 in the presence of different copolyamino acids.

Example BQ1: Preparation of a solution of pramlintide at 0.6 mg / ml and human insulin at 100 IU / ml at pH 6.6 containing co-polyamino acid AB14, m-cresol (29 mM), glycerin (174 mM), sodium chloride (100 mM) and zinc chloride (1 mM) [000612] A concentrated solution of AB14 co-polyamino acid and of excipients is prepared by adding concentrated solutions of excipients (m -cresol, glycerin, sodium chloride, zinc chloride) to a concentrated solution of co-polyamino acid

AB14.

177 [000613] A solution of pramlintide concentrated at 5 mg / ml at pH 4 and then a solution of human insulin at 500 IU / ml are added to this concentrated solution of copolyamino acid AB14 and of excipients so as to obtain the final composition targeted . The final pH is adjusted to 6.6 by adding NaOH / HCl.

The BQ1 solution is prepared according to the above protocol.

Example BQO: Preparation of a solution of pramlintide at 0.6 mg / ml and human insulin at 100 IU / ml containing different copolyamino acids of the invention, m-cresol (29 mM), glycerin (174 mM), and different contents of sodium chloride and zinc chloride [000617] By a process similar to Example BQO, solutions of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL containing different co-polyamino acids of the invention, m-cresol (29 mM), glycerin (174 mM), sodium chloride and zinc chloride at pH 6.6 are obtained.

The solutions BQ2 to BQ12 are prepared according to the above protocol.

Solution Co- polyamino Concentration in copolyamino [NaCl] [ZnCI ₂ ] Visual aspect of the solution mg / mL mM (MM) (MM) BQ1 AB14 6.3 1.87 100 1 limpid BQ2 AB15 7.8 1.6 0.23 limpid BQ3 AB15 GECA .......... 2.3 - 0.23 limpid BQ4 AB15 3.9 0.8 50 0.23 limpid BQ5 AB15 6.3 1.3 50 0.23 limpid BQ6 AB15 7.8 1.6 50 0.23 limpid BQ7 AB15 3.9 0.8 100 0.23 limpid BQ8 AB15 6.3 1.3 100 0.23 limpid BQ9 AB15 7.8 1.6 100 0.23 limpid BQ10 AB16 7.4 0.9 50 0.23 limpid BQ11 AB16 12.4 1.5 50 0.23 limpid BQ12 AB16 7.4 50 1 limpid

Table 20: Compositions and visual appearance of the solutions of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL pH 6.6 in the presence of different copolyamino acids and of different contents of sodium chloride and zinc chloride .

178 [000619] Example BZO: Preparation of a 0.6 mg / mL pramlintide solution containing DMPG m-cresol (29 mM), glycerin (174 mM) at pH 6.6 [000620] A solution concentrate of DMPG and excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin) to a concentrated solution of DMPG.

A concentrated pramlintide solution at 10 mg / ml is added to this concentrated solution of DMPG and of excipients so as to obtain the intended final composition. The final pH is adjusted to 6.6 by adding NaOH / HCl.

[000622]

Example BZ1: Preparation of a 0.6 mg / mL pramlintide solution containing DMPG (4.5 mM), phenol (30 mM), glycerin (174 mM) and glycylglycine (8 mM) at pH 7.4

Solution DMPG (MM) Pramlintide concentration (mg / mL) pH excipients Visual aspect of the solution BZO 4.5 0.6 6.6 m-cresol 29 mM Glycerin 174 mM limpid BZ1 4.5 0.6 7.4 phenol 30 mM Glycylglycine 8mM Glycerin 174 mM limpid

Table 21: Compositions and visual appearance of pramlintide solutions at 0.6 mg / mL in the presence of DMPG.

Example CAI: Preparation of a 1 mg / mL pramlintide solution containing m-cresol (20 mM), mannitoi (43 mg / mL), and a sodium acetate buffer, at pH 4 [000623] A concentrated solution pramlintide 10 mg / mL is added to a concentrated solution of excipients (m-cresol, mannitoi, sodium acetate) so as to obtain the final composition targeted. The final pH is adjusted to 4 by adding NaOH / HCl. The clear solution is filtered (0.22 μΜ) and introduced into 3 ml glass cartridges for injector pen.

Example CA2: Preparation of a 100 IU / mL solution of human insulin containing co-polyamino acid BB15 (10 mg / mL), m-cresol (29 mM), glycerin (174 mM) and chloride zinc (229 pM) at pH 6.6 [000624] A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, zinc chloride) to a concentrated solution of co-polyamino acid BB15.

179 [000625] A solution of human insulin at 800 IU / mL is added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to obtain the final composition targeted. The final pH is adjusted to 6.6 by adding NaOH / HCl. The clear solution is filtered (0.22 μΜ) and introduced into 3 ml glass cartridges for injector pen.

Example CA3: Preparation of a 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin containing co-polyamino acid BB15 (10 mg / mL), m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6 [000626] A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, zinc chloride) to a concentrated solution of co-polyamino acid BB15.

A concentrated solution of pramlintide at 10 mg / ml and then a concentrated solution of human insulin at 500 IU / ml are added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to obtain the intended final composition. The final pH is adjusted to 6.6 by adding NaOH / HCl. The clear solution is filtered (0.22 μΜ) and introduced into 3 ml glass cartridges for injector pen.

Results of visual observations of the mixture and of fibrillation measurements by ThT

Principle [000628] The poor stability of a peptide can lead to the formation of amyloid fibrils, defined as ordered macromolecular structures. These can possibly result in the formation of gel within the sample.

The test for monitoring the fluorescence of thioflavin T (ThT) is used to analyze the physical stability of the solutions. Thioflavin is a small probe molecule with a characteristic fluorescence signature when it binds to amyloid-like fibrils (Naiki et al. (1989) Anal. BioChem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284).

This method makes it possible to monitor the formation of fibrils for low concentrations of ThT in undiluted solutions. This monitoring is carried out under accelerated stability conditions: with stirring and at 37 ° C.

Experimental conditions [000631] The samples were prepared just before the start of the measurement. The preparation of each composition is described in the associated example. Thioflavin T

180 was added to the composition from a concentrated stock solution so as to induce a negligible dilution of the composition. The concentration of Thioflavin T in the composition is 1, 2 or 40 μΜ depending on the type of composition: 40 μΜ in the case of human amylin compositions at 0.6 mg / mL, 2 μΜ in the case of pramlintide compositions at 0.9 mg / mL and 1 μΜ in the pramlintide compositions at 0.4 mg / mL. This concentration is recalled in the legend relating to the table of results of the latency times for each type of composition.

[000632] A volume of 150 μL of the composition was introduced into a well of a 96-well plate. Each composition was analyzed in three tests (triplicate) within the same plate. The plate was sealed with transparent film to avoid evaporation of the composition.

[000633] This plate was then placed in the enclosure of a plate reader (EnVision 2104 Multilabel, Perkin Elmer). The temperature is adjusted to 37 ° C., and lateral agitation of 950 rpm with 1 mm of amplitude is imposed.

[000634] A reading of the fluorescence intensity in each well is carried out with an excitation wavelength of 442 nm, and an emission wavelength of 482 nm over time.

The fibrillation process is manifested by a sharp increase in fluorescence after a delay called lag time.

For each well, this delay was determined graphically as the intersection between the baseline of the fluorescence signal and the slope of the fluorescence curve as a function of the time determined during the large initial increase in fluorescence. The latency time value reported corresponds to the average of the latency time measurements made on three wells.

An example of graphical determination is shown in FIG. 1.

In this figure is shown graphically the determination of the latency time (LT) by monitoring the fluorescence of Thioflavin T, on a curve having on the ordinate the value of fluorescence (in ua arbitrary units) and on the abscissa time in minutes.

181

Example C1: Stability of human amylin solutions at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio BB15 / human amylin e BB15 copolyamino acid concentration Standby time (hour) mol / mol mg / ml mM BV1 - • i <0.02 BV5 5 3 0.73 > 1 BV6 6 3.6 0.88 > 5 BV7 7 4.2 1.03 > 30 BV8 8 4.8 1.17 > 54 BV9 9 5.4 1.32 > 54 BV10 10 6 1.47 > 72

Table 22: Measurement of the latency time by ThhT (40 μΜ) of solutions BV1 to BV10.

The latency time of a human amylin solution at pH 7.4 (BV1), devoid of co-polyamino acid, is less than 0.02 hours; the BV5 to BV10 solutions according to the invention, containing BB15 / human amylin molar ratios greater than 5 make it possible to obtain latency times greater than one hour, a molar ratio of 10 making it possible to obtain latency times greater than 72 hours.

Example C2: Stability of solutions of human amylin and of human insulin 100 IU at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio BB15 / human amylin e BB15 copolyamino acid concentration Standby time (hour) mol / mol mg / mL mM BX1 ~ - - * BX6 6 3.6 0.88 > 0.1 BX10 10 6 1.47 > 0.5 BX11 "17.5 10.5 2.57 > 5

* Latency time not measured because turbid solution

Table 23: Measurement of the latency time by ThhT (40 μΜ) of the solutions, BX6, BX10 and BX11.

The solution of human amylin and human insulin at pH 7.4 (BX1) is turbid. The co-polyamino acid BB15 makes it possible to obtain a clear solution containing human amylin in the presence of human insulin at pH 7.4 with times of

182 latency greater than 0.1 hour from a BB15 / human amylin molar ratio of 6, and greater than 5 hours for a BB15 / human amylin molar ratio of 17.5.

Example C3: Stability of 0.4 mg / ml solutions of pramlintide at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Co-polyamino acid BB15 concentration BB15 / pramlintide ratio Latency (Hours) mg / mL mM mol / mol BW1 - • 0.7 BW2 2.4 0.59 6 > 40 BW3 4 0.98 10 > 53

Table 24: Measurement of the latency time by ThhT (1 μΜ) of solutions BW1 to BW3.

The pramlintide solution at pH 7.4 (BW1) devoid of co-polyamino acid has a short latency time. The BB15 co-polyamino acid makes it possible to obtain a solution containing pramlintide at pH 7.4 with latency times greater than 40 hours from a BB15 / pramlintide molar ratio of 6.

Example C4: Stability of solutions at 0.9 mg / ml of pramlintide at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio BB15 / pramlintide Concentration in BB15 Latency (Hours) mol / mol mg / ml mM BY1 : - - - 0.7 BY2 2 . ....... Μ 0.44 > 0.8 BY3 3 2.7 0.66 > 4 BY4 4 3.6 0.88 > 30 BY5 5 4.5 1.10 > 63 by6 6 5.4 1.22 > 63 BY7 10 9 1.32 > 53

Table 25: Measurement of the latency time by THh (2 μΜ) of solutions BY1 to BY7 [000642] The pramlintide solution at pH 7.4 (BY1) devoid of co-polyamino acid has a short latency time; the latency times of the solutions containing a co-polyamino acid are greater than or equal to the latency times of the composition without co-polyamino acid at a molar ratio of co-polyamino acid BB15 / pramlintide of 2: 1.

183

Example C5: Stability of pramlintide solutions at 0.9 mg / m! at pH 7.4 in the presence of different co-polyamino acids.

Solut ion Copoly amin oacid e Concentration in copolyamino Copolyamino acid / pr amlintide ratio Standby time (hours) mg / ml mM mol / mol BY1 - <0.7 BP2 BB15 5 10 1.22 2.45 5.4 10.8 > 63 > 63 BP3 BB14 10 1.96 8.6 > 15 BP4 AB17 10 1.22 9.8 > 63 BP10 BB18 5 10 0.72 1.44 3.2 6.3 > 63 > 63 BP11 BB9 5 10 1 2.01 4.4 8.8 > 50 > 63 BP12 BB2 5 10 1.27 2.54 5.6 11χ2 i > 10 > 63

Table 26: Measurement of the latency time by THh (2 μΜ) of the compositions BY1, BP2 to

BP12.

The pramlintide solution at pH 7.4 (BY1) devoid of co-polyamino acid has a short latency time. The co-polyamino acids of the invention make it possible to obtain latency times greater than 1.9 hours under the conditions tested.

Example CB1: Stability of solutions at 0.6 mg / mL of pramlintide at pH 6.6 in the presence of co-polyamino acid BB15 at different concentrations. * 000644]

Solution Ratio BB15 / pramlintide BB15 copolyamino acid concentration Latency (H) mol / mol mg / mL mM BH1 - - - 1 BH2 2 1.3 0.29 > 4 BH3 3 2 0.45 > 10 BH4 4 2.7 0.61 > 50 BH5 6 4 0.90 > 50 BH6 8 5.3 1.19 > 50 BH7 10 6.7 1.50 > 50 BH8 15 10 2.24 > 50

Table 27: Measurement of the latency time by THh (2 μΜ) of the BH1 and BH2 solutions at

BH8 [000645] The pramlintide solution at pH 6.6 (BH1) devoid of co-polyamino acid exhibits a short latency time; the latency times of solutions containing a

184 co-polyamino acids are greater than the latency times of the composition without copolyamino acid at a molar ratio of co-polyamino acid BB15 / pramlintide of 2: 1.

Example CB2: Stability of pramlintide solutions at 0.6 mg / ml at pH 6.6 in the presence of different co-polyamino acids.

Solution copolyamino Copolyamino acid concentration Ratio co- polyamino / pramlintide Latency (h) mg / mL mM mol / I DRANK BB20 1.3 2.6 0.3 0.6 2 4 > 10 > 20 BI2 BB21 1.3 0.6 4 > 10 BI 3 AB22 2.4 0.3 2 > 10 BI4 BB24 . 2.9 . 0.6 4 > 10 BIN5 BB25 1.5 3 0.3 0.6 2 4 > 50 > 50 BI6 AB23 3.4 0.23 2 > 10 BI7 AB28 2.3 4.7 0.3 0.6 2 4 > 10 > 10 BI8 AB24 1.2 _n ................. 2.4 ....... 0.15 0.3 1 2 > 10 > 50 BI9 AB25 1.3 2.6 0.15 0.3 1 2 > 10 > 10 BI10 AB26 i, O 0.3 2 > 10 Bill AB27 1.3 2.7 0.15 0.3 1 2 > 5 > 10 BI12 AB31 1.3 ^ 2.5 ............. 0.15 0.3 1 2 > 10 > 10 BI13 AB29 8.9 1.15 7.6 > 5 BI14 AB32 1.3 2.5 0.15 0.3 1 2 > 10 > 10 Table 28: Latency measurement by temps ΓήΤ (2 μΜ) of compositions B] [1 to BI14

The pramlintide solution at pH 6.6 (BH1) devoid of co-polyamino acid has a short latency time. The co-polyamino acids of the invention make it possible to obtain latency times greater than 6 h under the conditions tested.

185

Example CB3: Stability of pramlintide solutions at 0.6 mg / ml at pH 6.6 in the presence of co-polyamino acid AB14 and of different contents of sodium chloride and zinc chloride.

Solution Copolyaminoa eide Concentration in copolyaminoac ide Ratio œ- polyamino acid / praml intide [NaC 1] [ZnCl 2] Temp s of iaten ce (h) mg / m The mM mol / mol (mM ) (MM) BT1 AB14 6.3 1.87 12 0.75 0.6 BT2 AB14 6.3 1.87 12 50 - > 2 BT3 AB14 6.3 1.87 12 100 - > 5 BT4 AB14 6.3 1.87 12 50 0.75 > 5 BT5 AB14 6.3 1.87 12 100 0.75 > 20

Table 29: Measurement of the latency time by ThT (2 μΜ) of the compositions BT1 to BTS [000647] The solution of pramlintide at pH 6.6 and of co-polyamino acid AB14 has a longer latency time in the presence of sodium chloride or sodium and zinc chloride.

Example CB4: Stability of pramlintide solutions at 0.6 mg / ml at pH 6.6 in the presence of different co-polyamino acids and of different contents of sodium chloride and zinc chloride.

Solution copolyamino Copolyamino acid concentration [NaCl] [ZnCI ₂ ] Latency (H) mg / mL mM (MM) (MM) BS1 AB15 7.8 1.6 * 3.5 BS2 AB15 . .11.7 2.3 - . .. i > 30 BS3 AB15 ¹ 3.9 0.8 50 > 10 BS4 Γγ ···; ...... 6.3 1.3 50 - > 50 BS5 AB15 7.8 1.6 50 > 30 BS6 AB15 3.9 0.8 100 > 50 BS7 AB16 12.4 1.5 8 BS8 AB16 16.7 2.1 ; > 50 BS9 AB16 ......... 7.4 ....... 0.9 50 > 20 BS10 AB16 12.4  AT 50 > 50 BS11 AB16 7.4 50 1 > 30

Table 30: Measurement of the latency time by ThT (2 μΜ) of the compositions BS1 to

BS11

186 [000648] The solutions of pramlintide at pH 6.6 and of co-polyamino acid AB15 and AB16 have a longer latency in the presence of sodium chloride or sodium chloride and zinc.

Example C6: Stability of solutions of pramlintide at 0.4 mg / ml and of human insulin 100 IU / ml at pH 7.4 containing co-polyamino acid BB15.

Solution BB15 copolyamino acid concentration BB15 / pramlintide ratio Standby time (hour) mg / mL mM mol / mol 6 ^ 1 ^--- H - - * BN2 2.4 0.59 6 > 19 BN3 4 0.98 10 > 19

* Latency time not measured because turbid solution.

Table 31: Measurement of the latency time by THh (1 μM) of the compositions BN1 to BN3.

The pramlintide and human insulin solution at pH 7.4 (BN1) devoid of co-polyamino acid is turbid.

[000650] The co-polyamino acid BB15 makes it possible to obtain a clear solution of pramlintide at 0.4 mg / ml and of human insulin 100 IU / ml at pH 7.4 with latency times greater than 19 hours for ratios BB15 / pramlintide molars greater than 6.

Example C7: Stability of solutions of pramlintide at 0.9 mg / ml and of human insulin 100 IU / ml at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio BB15 / pramlintide BB15 copolyamino acid concentration Standby time (hour) mol / mol mg / ml mM BIS - - - * BU3 2 1.8. 0.44 > 0.5 BR2 3 2.7 0.66 > 2 BR3 4 3.6 0.88 > 6 BR4 5 4.5 1.10 > 9 BU7 6 5.4 1.32 > 9 BU8 10 9 2.20 > 9

* Latency time not measured because turbid solution.

187

Table 32: Measurement of the latency time by THh (2 μΜ) of the BRI solution at BR4 and BU3 at BU8.

[000651] A solution of pramlintide at 0.9 mg / ml and of human insulin 100 IU / ml at pH 7.4 (BRI) devoid of co-polyamino acid is turbid. The clear solutions of pramlintide at 0.9 mg / ml and of human insulin 100 IU / ml at pH 7.4 in the presence of copolyamino acid BB15 have latency times greater than 0.5 hour at molar ratio BB15 / pramlintide of 2 , which may be greater than 9 hours for BB15 / pramlintide molar ratios greater than 5.

Example C8: Stability of solutions of pramlintide at 0.9 mg / ml and of human insulin 100 IU / ml at pH 7.4 in the presence of different co-polyamino acids.

Solut ion Copolya minoa eide Copolyamino acid concentration Ratio co- polyamino acid / pramli ntide Standby time (hours) mg / m The mM mol / mol BIS "* * BG2 BB15 5 10 1.22 2.45 5.4 10.8 > 9 > 7 BG3 BB14 10 1.96 8.6 > 9 BG4 AB17 5 10 1.11 1.22 4.9 9.8 > 2 > 5 BG5 AB15 10 1.99 8.8 > 2 BG10 BB18 5 10 0.72 1.44 3.2 6.3 > 1 > 4 BG11 BB9 5 10 1 2.01 4.4 8.8 > 4 > 3 BG12 BB2 5 10 1.27 2.54 5.6 11.2 > 5 > 6

* Latency time not measured because turbid solution.

Table 33: Measurement of the latency time by THh (2 μΜ) of solutions BG1 to BG13.

188 The solution of pramlintide and human insulin at pH 7.4 (BRI) is turbid. The co-polyamino acids make it possible to obtain latency times greater than 1 hour under the conditions tested.

Example C9: Stability of solutions of pramlintide at 0.9 mg / ml and insulin lispro 100 IU / ml at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio BB15 / pramlintide BB15 copolyamino acid concentration Latency (Hours) mol / mol mg / ml mM BD1 - - * BD3 2 l _t 8 0.44 0.8 BD4 3 2.7 0.66 > 2 BD5 4 3.6 0.88 > 7 BD6 5 4.5 ï 10 > 9 BD7 6  5.4 1.22 > 9 BD8 10 9 .................... 1.32J > 9

* Latency time not measured because turbid solution.

Table 34: Measurement of the latency time by ThT (2 μΜ) of the BD1 and BD3 to BD8 solutions.

The pramlintide and insulin lispro solution at pH 7.4 (BD1) is turbid. The co-polyamino acids make it possible to obtain latency times greater than 0.8 hours under the conditions tested.

Example CB5: Stability of solutions of pramlintide at 0.6 mg / ml and of human insulin 100 IU / ml at pH 6.6 in the presence of co-polyamino acid BB15 at different concentrations ^

Solution Ratio BB15 / pramlintide BB15 copolyamino acid concentration Latency (H) mol / mol mg / mL mM BK1 " * BK3 3 2 0.45 > 0.5 BK4 4 2.7 0.61. > 5 BK5 6 4 0.90 > 5 BK6 8 5.3 1.19 > 5 BK7 10 6.7 1.50 > 5 BK8 15 10 2.24 > 5 *Time to atence not measured because turbid solution.

Table 35: Measurement of the latency time by ThT (2 μΜ) of the solutions BK1 and BK2 to BK8 The solution of pramlintide and human insulin at pH 6.6 (BK1) is turbid.

Clear solutions of pramlintide 0.6 mg / ml and human insulin 100 IU / ml at pH

189

6.6 in the presence of co-polyamino acid BB15 have latency times greater than 0.5 h at a BB15 / pramlintide molar ratio of 3, which can be greater than 5 h from a BB15 / pramlintide ratio of 4.

Example CB6: Stability of solutions of pramlintide at 0.6 mg / ml and of human insulin 100 IU / ml at pH 6.6 in the presence of different co-polyaminocacids.

Solution Co- polyamino Concentration in copolyamino acid Ratio co- polyamino / pramlintide Latency (H) mg / mL mM mol / mol BMI BB20 2.6 i 0.61 4 > 1 5.3 1.22 8 > 1 BM2 BB21 1.3! 0.6 4 > 10 BM3 AB22 2.4 | 0.3 2 > 5 BM4 BB24 2.9 I 0.6 4 > 10 BM5 BB23 3 i 0.76 5 > 10 6MT BB25 1.5 i 0.3 2 > 10 BM7 BB22 2.7 i 0.6 4 > 5 BM8 AB23 7.7 0.69 4.6 > 15 BM9 BB19 4.7 0.4 2.8 > 1 BM10 AB28 2.3 0.3 2 > 10 BMI1 AB24 2.4 i 0.3 2 > 5 BM12 AB25 2.6 i 0.3 2 > 5 BM13 AB26 1.5 0.3 2 > 1 2.3 0.5 3 > 10 BM14 AB27 1.3 i 0.15 1 > 1 2.7 0.3 2 > 5 BM15 AB30 1.2 0.15 1 > 1 2.3 t 0.3 2 > 10 BM16 AB31 1.3 0.15 1 > 1 2.5 0.3 2 > 10 BM17 AB29 5.9 ¹ 0.8 5 > 1 8.9 1.15 7.6 > 5 BM18 AB32 2.5 | 0.3 2 > 1

Table 36: Measurement of the latency time by ThT (2 μΜ) of the solutions and BMI at BM18 [000655] The solution of pramlintide and human insulin at pH 6.6 (BK1) is turbid. The co-polyamino acids make it possible to obtain latency times greater than 1 hour under the conditions tested.

190

Example CB7: Stability of solutions of pramlintide at 0.6 mg / ml and of human insulin 100 IU / ml at pH 6.6 in the presence of different co-polyamino acids and of different contents of sodium chloride and zinc chloride.

Solution copolyamino Copolyamino acid concentration [NaCl] [ZnCI ₂ ] Latency (H) mg / ml mM (MM) (MM) BQ1 AB14 6.3 1.87 100 1 > 5 BQ2 AB15 7.8 1.6 0.23 > 2 BQ3 AB15 11.7 .. 2.3. 0.23 > 2 . ... BQ 5 ... ......... ΑΒ15 ₌ ^, _ί 6.3 . .1,3 50 0.23 > 2 BQ6 AB15 7.8 1.6 50 0.23 > 5 BQ7 AB15 3.9 0.8 100 0.23 > 2  BQ8 ..... AB15 6.3 1.3 100 0.23 > 2 BQ9 AB15 7.8 1.6 100 0.23 > 5 BQ10 AB16 7.4 0.9 50 0.23 > 1 BQ11 AB16 12.4 l _t 5 50 0.23 > 2 BQ12 AB16 Δ 4) 0.9 50 1 > 2

Table 37: Measurement of the latency time by Thh (2 μΜ) of solutions BQ1 and BQ2 to BQ12 [000656] The solutions of pramlintide and human insulin at pH 6.6 in the presence of the co-polyamino acids of AB14, AB15 and AB16, of sodium chloride and zinc have latency times greater than 1 hour under the conditions tested. Adding sodium chloride or sodium chloride and zinc increases the latency times.

Study of the stability of the compositions according to the invention

Example ALPHA: Preparation of a 0.9 mg / mL pramlintide solution containing m-cresol (29 mM) and glycerin (174 mM) at pH 6.6.

By a process similar to that used in Example BH1 a solution of pramlintide at 0.9 mg / ml containing m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 is obtained .

191

Example DELTA: Preparation of a pramlintide solution at 0.9 mg / mL containing co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6.

By a process similar to that used in example BHO, a solution of pramlintide at 0.9 mg / mL and co-polyamino acid BB15 at 10 mg / mL containing m-cresol (29 mM) and glycerin (174 mM ) at pH 6.6 is obtained.

Visual inspection procedure:

The vials or 3 mL cartridges filled with 1 mL of formulation are visually inspected to detect the appearance of visible particles or turbidity. This inspection is carried out according to the recommendations of the European Pharmacopoeia (EP 2.9.20): the vials are subjected to lighting of at least 2000 Lux and are observed in front of a white background and a black background. The number of weeks or months of stability corresponds to the time from which the solutions contain visible particles or are turbid.

These results are in agreement with the US Pharmacopoeia (USP <790>).

Formulation dosing procedure:

The quantification of the purity of pramlintide and of insulin and of the recovery of native peptide is carried out by reverse phase HPLC equipped with a CA18 column of dimension 4.6 x 150 mm with a particle size of 3, 5 μΜ. Pramlintide is detected at a wavelength of 214 nm and insulin is detected at a wavelength of 276 nm. The elution is carried out in an aqueous mobile phase with a linear gradient of acetonitrile.

The overlap of pramlintide and insulin (%) at time t represents the ratio between the area of the pramlintide peak at time t and the area of the initial pramlintide peak.

The purity of pramlintide and insulin (%) represents the ratio between the area of the absorbance peak of pramlintide and the total area of all the peaks including pramlintide and its impurities.

Example CD1: Physical stability in cartridges at 37 ° C. of pramlintide solutions at 0.9 mg / ml in the presence of co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 or pH 7.4.

Alpha, BY-1, Delta and BY-7 solutions are filtered (0.22 μΜ). 1 mL of solution is introduced into a 3 mL glass cartridge for an auto-injector pen. Cartridges

192 are placed in a static oven at 37 ° C. The cartridges are observed with a weekly frequency.

(000661]

Solution BB15 copolyamino acid concentration pH Physical stability 37 ° C in cartridges (weeks) mg / ml Alpha / .... ........ 6.6 <1 BY-1 · 7.4 <1 Delta 10 6.6 > 4 BY-7 10 YOUR > 4

The pramlintide solutions at 0.9 mg / ml at pH 6.6 and pH 7.4 have physical stability at 37 ° C. in cartridges for less than a week.

The pramlintide solutions at 0.9 mg / ml at pH 6.6 and pH 7.4 in the presence of co-polyamino acid BB15 have physical stability at 37 ° C in cartridges of at least 4 weeks.

[000665]

Example CD2: Chemical stability in cartridges at 37 ° C. of pramlintide solutions at 0.9 mg / mL in the presence of co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 and 7.4.

The solutions described in Example CD1 are analyzed by RP-HPLC chromatography.

L000666]

Solution Co-polyamino acid BB15 concentration pH Pramlintide recovery (%) 32 days - 37 ° C Purity pramlintide (%) mg / mL TO 32 days 37 ° C Alpha j 6.6 <60 97.2 <50 BY-1 j 7.4 <20 94.7 <50 Delta _1Q -— ~ 6.6 > 90 97.8 > 60 BY-7 10 7.4 > 60 98.6 > 60

The pramlintide solutions at 0.9 mg / mL at pH 6.6 and pH 7.4 have a pramlintide coverage of less than 60% and the purity of pramlintide is less than 50% after 32 days at 37 ° C. in cartridge.

The pramlintide solutions at 0.9 mg / ml at pH 6.6 and pH 7.4 in the presence of co-polyamino acid BB15 have an overlap greater than 65% and which can be greater than 90% at pH 6.6 after 32 days at 37 ° C in cartridges. In the presence of co-polyamino acid BB15, the purity of pramlintide is greater than 65% and can be greater than 85% at pH 6.6.

193

Example CD3: Physical stability in vial and cartridge at 30 ° C. of solutions of pramlintide at 0.9 mg / ml and at 0.6 mg / ml in the presence of the co-polyamino acid BB15, of m-cresol (29 mM) and of glycerin (174 mM) at pH 6.6.

The Alpha, BH1, Delta and BH8 solutions are filtered (0.22 μΜ). 1 mL of solution is introduced into 3 mL glass cartridges for auto-injector pen and into 3 mL glass vials. The cartridges and the vials are placed in a static oven at 30 ° C and are then observed every 2 weeks.

Solution BB15 copolyamino acid concentration Concentration pramlintide pH Stability physical 30 ° C in via! (Weeks) Physical stability 30 ° C in cartridge (weeks) mg / mL (Mg / mL) Alpha - 0.9 6.6 <7 <2 BH1 - 0.6 6.6 <7  -: Delta 10 0.9 .. 6.6 > 12 > 12 BH8 10 0.6 6.6 > 12 Γ '> 12

The pramlintide solutions at 0.9 mg / mL and 0.6 mg / mL at pH 6.6 have physical stability in vial of less than 7 weeks at 30 ° C. The physical stability in a cartridge of the pramlintide solution at 0.9 mg / mL pH 6.6 is less than 2 weeks. The pramlintide solutions at 0.9 mg / ml and 0.6 mg / ml at pH 6.6 in the presence of co-polyamino acid BB15 have physical stability at 30 ° C greater than 12 weeks in vial and in cartridge .

Example CD4: Chemical stability in vial at 30 ° C. of solutions of pramlintide at 0.9 mg / ml and at 0.6 mg / ml in the presence of the co-polyamino acid BB15, of mresol (29 mM) and of glycerin (174 mM ) at pH 6.6.

The solutions described in Example CD3 are analyzed by RP-HPLC chromatography.

Solution BB15 copolyamino acid concentration Pramlintide concentration Pramlintide recovery (%) Pramlintide purity (%) mg / mL (Mg / mL) 5 weeks 30 ° C T0 5 weeks 30 ° C Alpha - 0.9 <70 97.2 <60 Delta 10 0.9 > 95 97.8 > 90 BH8 10 0.6 > 95 94.6 > 90

The pramlintide solution at 0.9 mg / mL at pH 6.6 has a pramlintide coverage of less than 70% and the purity of pramlintide is less than 60% after 5 weeks at 30 ° C in vial.

194 The solutions of pramlintide at 0.9 mg / ml and 0.6 mg / ml at pH 6.6 in the presence of co-polyamino acid BB15 have a pramlintide coverage greater than 95% and the purity of pramlintide is greater 90% after 5 weeks at 30 ° C.

[000673]

Example CD5: Physical stability in vial and cartridges at 30 ° C of solutions of pramlintide at 0.6 mg / mL and insulin 100 IU / mL at pH 6.6 in the presence of copolyamino acid BB15, of m-cresol (29 mM ), glycerin (174 mM) and zinc at pH 6.6.

The BK8 solution is filtered (0.22 μΜ). 1 mL of solution is introduced into 3 mL glass cartridges for auto-injector pen and into 3 mL glass vials. The cartridges and vials are placed in a static oven at 30 ° C and are then observed every 2 weeks.

Solutio not Concentration co ~ polyaminoacid e BB15 Pramlintide concentration Insulin Concentration Physical stability 30 ° C in vial (weeks) Physical stability 30 ° C in cartridge (weeks) mg / mL (Mg / mL) (IU / mL) BK1 - 0.6 100 * BK8 10 0.6 100 > 3 > 12

^ turbid solution as soon as it is prepared.

The solution of pramlintide at 0.6 mg / mL and insulin at 100 lU / mL at pH 6.6 is turbid.

The solution of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL at pH 6.6 in the presence of co-polyamino acid BB15 has physical stability at 30 ° C greater than 3 weeks in vial and more than 12 weeks in cartridge.

195

Example CD6: Chemical stability in vial at 30 ° C of solutions of pramlintide at 0.6 mg / ml and insulin 100 IU / ml at pH 6.6 in the presence of the co-polyamino acid BB15, of m-cresol (29 mM ), glycerin (174 mM) and zinc at pH 6.6.

The solutions described in Example CD6 are analyzed by RP-HPLC chromatography.

Solution Pramlintide recovery (%) Pramlintide purity (%) Recovery Insulin (%) Purity Insulin (%) 5 weeks 30 ° C T0 5 weeks 30 ° C 5 weeks 30 ° C T0 5 weeks 30 ° C BK8 92.8 > 90 > 90 97.9 > 90

The solution of pramlintide at 0.6 mg / mL and insulin at 100 IU / mL at pH 6.6 in the presence of co-polyamino acid BB15 have a pramlintide coverage greater than 90% and the purity of pramlintide is greater than 92% after 5 weeks at 30 ° C in vial. The insulin recovery is greater than 92% and the purity of the insulin is greater than 92% after 5 weeks at 30 ° C in vial.

[000677]

Example CD7: Physical stability in vial at 30 ° C and cartridge at 30 ° C / 37 ° C of solutions of pramlintide at 0.6 mg / mL and insulin 100 IU / mL at pH 6.6 in the presence of co- polyamino acid AB24 at 2.4 mg / mL, m-cresol (29 mM), glycerin (174 mM) and zinc at pH 6.6.

The BM11 solution is filtered (0.22 μΜ). 1 mL of solution is introduced into 3 mL glass cartridges for auto-injector pen and into 3 mL glass vials. The cartridges and vials are placed in a static oven at 30 ° C and are then observed every 2 weeks. Cartridges are also placed in an oven at 37 ° C static and are observed every week.

Soluti we Concentratio n co- polyaminoac ide AB24 Concentrate! we pramlintide Concentrate! we Insulin Physical stability 30 ° C in vial (week s) Physical stability 30 ° C in cartridge (week s) Physical stability 37 ° C in cartridge (week s) mg / mL (Mg / mL) (IU / mL) BK1 - 0.6 100 * * * BM11 . -2.4 0.6 100 > 9 > 12 > 9

* turbid solution as soon as it is prepared.

196 [000678] The solution of pramlintide at 0.6 mg / mL and insulin at 100 IU / mL at pH 6.6 is turbid.

The solution of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL at pH 6.6 in the presence of co-polyamino acid AB24 has physical stability at 30 ° C greater than 9 weeks in vial and more than 12 weeks in cartridge. Physical stability at 37 ° C in cartridge is greater than 9 weeks.

Example CD8: Chemical stability in vial and cartridge at 30 ° C of solutions of pramlintide at 0.6 mg / mL and insulin 100 IU / mL at pH 6.6 in the presence of copolyamino acid AB24 at 2.4 mg / mL, m-cresol (29 mM), glycerin (174 mM) and zinc at pH 6.6.

The solutions described in Example CD7 are analyzed by RP-HPLC chromatography.

Solution BM11 Pramlintide recovery (%) Pramlintide purity (%) Insulin recovery (%) Purity Insulin (%) 9 weeks 30 ° C TO 9 weeks 30 ° C 9 weeks 30 ° C TO 9 weeks 30 ° C Vial 89.5 96.7 > 90 > 90 97.4 > 90 Cartridge 88.8 96.9 > 85 > 90 97.7 > 90

The pramlintide solution at 0.6 mg / mL and human insulin at 100 IU / mL at pH 6.6 in the presence of co-polyamino acid AB24 has a pramlintide coverage greater than 88% and a purity greater than 89% after 9 weeks of storage at 30 ° C in vial and in cartridge. Under these conditions, the insulin recovery is greater than 92% and the purity of insulin greater than 91% in vial and in cartridge.

Example CD9: Physical stability in a cartridge at 4 ° C. of solutions of pramlintide at 0.6 mg / ml at pH 6.6 in the presence of the co-polyamino acid BB15, of m-cresol (29 mM), of glycerin (174 mM) at pH 6.6.

The BH8 solution is filtered (0.22 μΜ). 1 mL of solution is introduced into 3 mL glass cartridges for auto-injector pen. The cartridges are placed in a refrigerator at 4 ° C.

197

Solution BB15 copolyamino acid concentration Pramlintide concentration pH Physical stability 4 ° C in cartridge (months) mg / mL (Mg / mL) BH8 10 0.6 6.6 > 6

The pramlintide solution at 0.6 mg / mL and human insulin at 100 IU / mL at pH 6.6 in the presence of co-polyamino acid BB15 has physical stability in cartridges greater than 6 months.

Example CD10: Physical stability in a cartridge at 4 ° C. of pramlintide solutions at 0.6 mg / ml at pH 6.6 and pH 7.4 in the presence of DMPG at 4.5 mM [000683] The BZO and BZ1 solutions are filtered (0.22 μΜ). 1 mL of solution is introduced into 3 mL glass cartridges for auto-injector pen. The cartridges are placed in a refrigerator at 4 ° C.

Solution DMPG (MM) Pramlintide concentration (mg / mL) pH excipients Physical stability at 4 ° C in cartridges (months) BZO 4.5 0.6 6.6 m-cresol 29 mM Glycerin 174 mM <1.5 BZ1 4.5 0.6 7.4 phenol 30 mM Glycylglycine 8mM pH 7.4 Glycerin 174 mM <1.5

Claims (12)

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) amylin, an amylin receptor agonist or an amylin analog; b) a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic Hy radicals being of formula I below: * - ^ GpR ^ - ^ GpA ^ —Gpcj ^ra P Formula I in which GpR is a radical of formulas II or II ': H H * —N — R — N— * n * or O HE H R-N- * n '; GpA is a radical of formulas III or ΙΙΓ: O HN— * HN- * ni or H A-N— * ni '; - GpC is a radical of formula IV: - the * indicate the sites of attachment of the different groups linked by amide functions; a is an integer equal to 0 or 1; - b is an integer equal to 0 or 1; p is an integer equal to 1 or 2 and o if ρ is equal to 1 then a is equal to 0 or 1 and GpA is a radical of formula ΙΙΓ and, o if p is equal to 2 then a is equal to 1 , and GpA is a radical of formula III; - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2; - d is an integer equal to 0, 1 or 2; - r is an integer equal to 0 or to 1, and o if r is equal to 0 then the hydrophobic radical of formula I is linked to the copolyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in position N end of the copolyamino acid, thus forming an amide function resulting from the reaction of an amine function in the N terminal position of the co-polyamino acid precursor and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1 then the hydrophobic radical of formula I is linked to the copolyamino acid: • via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amine function of the precursor of the hydrophobic radical and an acid function carried by the precursor of the co-polyamino acid or • via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and an amine function in the N-terminal position carried by the precursor of the copolyamino acid; - R is a radical chosen from the group consisting of: o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 12 carbon atoms or if GpR is a radical of formula ΙΓ of 1 to 11 carbon atoms; o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 11 carbon atoms or if GpR is a radical of formula ΙΓ of 1 to 11 carbon atoms, said alkyl radical carrying one or more -CONH2 functions, and o an ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms; - A is a linear or branched alkyl radical comprising from 1 to 6 carbon atoms; - B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms; - C _x is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and: o if p is equal to 1, x is between 11 and 25 (11 <x <25): o if p is equal to 2, x is between 9 and 15 (9 <x <15), the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <i <0 , 5; - When several hydrophobic radicals are carried by a co-polyamino acid then they are identical or different, the degree of polymerization DP in glutamic or aspartic units is between 10 and 250; the free acid functions being in the form of an alkaline cation salt chosen from the group consisting of Na ⁺ and K ⁺ ; characterized in that the composition does not comprise a basal insulin whose Isoelectric point pi is between 5.8 and 8.5. 2. Composition according to claim 1, characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which p = 1, represented by the following formula V: formula V GpR, GpA, GpC, r and a have the definitions given above. 3. Composition according to Claim 1, characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which a = 1 and p = 2, represented by the following formula VI: GpC) ² Formula VI in which GpR, GpA, GpC, r and a have the definitions given above. 4. Composition according to any one of the preceding claims, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII below: O ^H 7 formula VII in which, • D represents, independently, either a group -CHz- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, in which r = 1 and GpR is a radical of Formula II, • Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI in which r = 0 or r = 1 and GpR is a radical of Formula ΙΓ, 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, "R2 is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI in which r = 1 and GpR is a radical of Formula II, or an identical or different radical -NR'R, R 'and R being chosen from the group consisting of H, linear or branched or cyclic C2 to CIO alkyl, l e benzyl and said R ′ and R alkyl which may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, N and S, • X represents an H or a cationic entity chosen from the group comprising metallic cations; • η + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of copolyamino acid and 5 <n + m <250. 5. Composition according to claim 4, characterized in that the copolyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, in which Ri = RT and R2 = R'2, of formula VIIa: ^Hy Formula Vlla in which, - m, η, X, D and Hy have the definitions given above, RT is a radical chosen from the group consisting of an H, a linear C2 to CIO acyl group, a branched C3 to CIO acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate, - R'2 is 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 may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, IM and S. 6. Composition according to claim 4, characterized in that the copolyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n = 0 of formula Vllb below: 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 I, V or VI. 7. Composition according to any one of the preceding claims, characterized in that_ratio molair & co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog is greater than or equal to 1. 8. Composition according to any one of the preceding claims, characterized in that the amylin, agonist at the naked amylin receptor analog of amylin is amylin. 9. Composition according to any one of claims 1 to 7, characterized in that the amylin, amylin receptor agonist or amylin analog is pramlintide. 10. Composition according to any one of the preceding claims, characterized in that it further comprises a mealtime insulin. 11. Composition according to claim 10, characterized in that the copolyamino acid / lnsulin molar ratio is greater than or equal to 1. 12. Composition according to any one of claims 1 to 9, characterized in that said composition has a stability measured by ThT greater than that of a reference composition comprising amylin, an agonist at the amylin receptor or an amylin analog but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals.