FR3083086A1 - COMPOSITIONS IN THE FORM OF AN AQUEOUS INJECTION SOLUTION COMPRISING AMYLINE, AN AMYLINE RECEPTOR AGONIST OR AN AMYLINE ANALOG AND A CO-POLYAMINOACID - Google Patents

Abstract

The invention relates to a 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 a analog of amylin; b) a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, said co-polyamino acid comprising glutamic or aspartic units and said hydrophobic Hy radicals being of formula I below: characterized in that the composition does not comprise any a basal insulin with an isoelectric point pI of between 5.8 and 8.5. It also relates to a composition characterized in that it further comprises a mealtime 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 [Ό001] The invention relates to therapies by injection of amyine, d amylin receptor agonist or amyine 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 amyiine 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 pl 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 hydrophobic radicals according to the invention for stabilizing compositions of amyine, of amylin receptor agonist or of amine analog as well as amyine, amylin receptor agonist or amine 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 drastically changed the life expectancy of these patients. However, the glycemic control provided by exogenous insulin is not optimal, especially after taking a meal. This is linked to the fact that these patients produce glucagon after eating a meal, which leads to the destocking of part of the glucose stored in the liver, which is not the case in healthy people. This glucose production mediated by glucagon exacerbates the problem of regulating the glycemia of 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 amylin 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: Polymorphic 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 Amylin has developed an analog of i'amyline, le 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, one hour before the meal in order to improve postprandial blood sugar control. This peptide is formulated at acidic pH and is described to fibrillate 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. I! 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 in aqueous solution i'amyline, an analogue of amylin, or an amylin receptor agonist, with a mealtime insulin 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 mealtime insulin solutions have a pH close to neutral for reasons of chemical stability, i! 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 problems of safety 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 pramiintide 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 applicant, there is no satisfactory means which makes it possible to combine, in aqueous solution, a mealtime insulin and human amylin, an arylin 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 brakes for obtaining a pharmaceutical formulation with neutral pH based on arnyline and pramiintide, but also a brake for combining amylin or pramiintide with other pharmaceutical ingredients. active, in particular peptides or proteins.

The Applicant has noticed that, surprisingly, the copolyarnino acids according to the invention stabilize arylin compositions, agonist at the amyiine receptor or amyl analog like at a pH between 6 and 8 In fact, compositions comprising amyiine, an amyiine 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 amamyin, 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 agitation conditions which allow the phenomenon to accelerate, the latency time before the formation of fibrils by measuring the increase in fluorescence. The compositions according to the invention have a latency time before the formation of fibrils markedly greater than that of amamyin, 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:

* ~ f ”GpR VnGpA ^ Gpcj ^ra P Formula i in which

- GpR is a radical of formulas Π, ΙΓ or Π:

HH i? HOO ~ N ”~ R” N— tj _0LS * R ”N -“ ”u ' _or formula Π;

- GpA is a radical of formulas III or III ':

he h

HN · - * _{ni or nr} .

~ GpC is a radical of formula IV ·:

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

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

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

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

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

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

- r is an integer equal to 0, 1 or 2, and o if r is equal to 0 then the hydrophobic radical of formula I is linked to the copolyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in N-terminal position of the copolyamino acid, thus forming an amide function resulting from the reaction of an amine function in the N-terminal position of the co-polyamino acid precursor and an acid function carried by the precursor of the hydrophobic radical. and o if r is equal to 1 or 2. then the hydrophobic radical of formula 1 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 a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions - CONH2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more unsaturated rings or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;

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

o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 12 carbon atoms, if GpR is a radical of formula II 'of 1 to 11 carbon atoms or if GpR is a radical of formula II from 0 to 10 carbon atoms;

o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 11 carbon atoms, if GpR is a radical of formula ΙΓ of 1 to 11 carbon atoms or if GpR is a radical of formula II from 0 to 10 carbon atoms, said alkyl radical carrying one or more -CONH2 functions, and o an ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;

A is a radical chosen from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical comprising from 1 to 8 carbon atoms and optionally substituted by a radical resulting from a saturated, unsaturated or aromatic cycle;

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, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and:

o if p is equal to 1, x is between 9 and 25 (9 <x <25):

o if ρ 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 · pl is between 5.8 and 8.5.

In one embodiment, when r = 2 then the GpR group linked to PLG is chosen from the GpRs of formula IL [00023] In one embodiment, when r = 2 then the GpR group linked to PLG is chosen from the GpRs of formula II and the second GpR is chosen from the GpRs of formula II.

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

In one embodiment, one embodiment, when r = 2 then the group GpR Hé at PLG is chosen from the GpRs of formula II and the second GpR is chosen from the GpRs of formula IL

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

H H * —N — R —N— * n.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 2 of formula Xc ', as defined below: * —- GpR — GpR (GpA; - ( GpC) ^ap Formula Xc 'in which GpRi is a radical of formula II.

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

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

* —GpR ~ GpR - (GpAy— (GpCj ^{a P} Formula Xc 'in which GpRi is a radical of formula II.

OO * __ LL _R Jl_ * Formula Π in which GpR, GpA, GpC, R, a, and p have the definitions given above.

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

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

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

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

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms [00031] In one embodiment, Hy comprises more than 15 carbon atoms.

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 aqueous solution for injection 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 the hydrophobic radicals of formula I in which if ρ is equal to 1 and if x is less than or equal to 14 (x <14) then r = Or r = 1.

In one embodiment, the composition is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which if p is equal to 1 and if x is between 15 and 16 (15 <x < 16), then r = 1, [00039] 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 the hydrophobic radicals of formula I in which if p is equal to 1 then x is between 17 and 25 (17 <x <25 ).

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

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

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

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

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

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

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

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

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

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

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

*; 0 ^ ^x nh ₂ Formula XI * XV XV * 1 Vh ₂ Formula X2

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

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

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

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

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

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

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

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is an ether radical represented by the formula [00060] In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a polyether radical.

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

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

Formula X3 & Formula X4 * Formula X5 Formula X6

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

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

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

Formula X5 * Λ / x. * Formula X6

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Formula IVd

Formula IVe

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

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

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

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

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

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

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

X == ll * x == 13

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

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

X-- 16

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 1.7 and 1.8 carbon atoms.

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

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

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

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

'- (GpR f + GpA V- · GpC ^r ' ^has formula V

GpR, GpA, GpC, r and a have the definitions given previously, [00098] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which: r is equal to 1 (r = 1) and a is equal to 0 (a == 0).

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

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

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

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

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

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

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

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

[000107] In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.

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

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent linear alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more functions amide (-CONH2), [000110] In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas ci below:

i, ·. # ^ ·· Ύ o- ^ ^x nh ₂ Formula XI * Z '' z ^d X * Cr ^x nh ₂ Formula X2

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

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

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

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

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

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

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

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

O.

represented by the formula [000119] In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a polyether radical, [000120] In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.

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

, .o '' • ’’ S * I Formula X3 Formula X4 * , ΛΚ. • x Formula X5 Formula X6

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

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

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

* χ ° χ / Χ * Formula X5 & s. * Form 116

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

In one embodiment, the composition is characterized in that the hydrophobic radical of fornuile V is a radical in which R is a polyether radical of formula X6, [000127] In one embodiment, the composition is characterized in what the hydrophobic radical is a radical of formula V in which GpR is a radical of formula IL [000128] 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 Π.

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 I in which GpR is a radical of formula II, ΙΓ or Π, in which R is a divalent alkyl radical, comprising of 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

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

In one embodiment, the composition is characterized in that the hydrophobic radicai is a radicai of formula I in iaciie GpR is a radical of formula Π, II 'or II in which R is a radical chosen from the group consisting by the 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 I in which GpR is a radical of formula II, 11 'or II, in which R is a linear ether or polyether radical unsubstituted 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 I in which GpR is a radical of formula II, ΙΓ or II, in which R is an ether radical.

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

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

..Cl, of Formula X7.

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

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

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

Γ0001501 x-Qr '·' '' formulated e X3 :AT'  . o. * formulated e X4 * O. ^ * formulated e X5 ., .. O. 'Ό' XK * formulated e X6

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

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

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

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

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

X A (X. Formula X5 -AT- Formula X6

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

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

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

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, II or Π, in which R is a divalent linear alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONHz).

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

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, ΙΓ or II, in which R is a linear ether or non-polyether radical substituted comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

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

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

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

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

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

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

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

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 of the radicals represented

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

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

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

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

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

* ch ₃ : h ₃ c Eh ₃ i * * * ch ₃ ' i ch ₃ H ₃ c ^. * * & h ₃ c ^ h ₃ c ^x ^ 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 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 represented by the formulas below:

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

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

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

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

* x = ll * Λ 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 by the radicals represented by the formulas below:

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

ÇH ₃ '''' _O h ₃ x = 16

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 25 carbon atoms.

3.1 [000187] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula 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 18 and 25 carbon atoms.

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

In one embodiment, the composition is characterized in that 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 J — GpA — GpCy ^{r 2} Formula VI in which

GpR, GpA, GpC, ret 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 Π 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 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, ΙΓ or II, 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 Vï in which GpR is a radical of formula II, ΙΓ or Π, in which R is a divalent linear alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

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

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

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

[000207] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II in which R is 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 * [000210] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II, in which R is a 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, ΙΓ or II, in which R is a linear polyether radical comprising of 6 with 10 carbon atoms and 2 to 3 oxygen atoms.

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

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

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 a radical of formula Illb below represented:

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:

VJ ^b ® • Formula IVa * _x , iO _{o λ} kJ ' ^b ° Formula IVb J''y 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.

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 formulas IVd, IVe, and IVf below represented:

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 ia 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 c

Λ - ^ ch ₃ x ~ 9 '''''' CH ₃ x = - 11 •Fr 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 of radicals represented by the formulas below:

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

Ο

formula VII in which, * D independently represents either a -CH? - group (aspartic unit) or a group -CH2-CH2- (glutamic unit), * Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, "Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, or a radical chosen from the group consisting of an H, a linear acyl group in C2 to CIO. a branched acyl group at C3 to CIO, a benzyl, a terminal “amino acid” unit and a pyroglutamate, “R2 is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI, or a radical -NR'R, R 'and R identical or different being chosen from the group consisting of H, linear or branched or cyclic C2 to CIO alkyls, benzyl and said R' and R alkyls which can together form one or more saturated, unsaturated and / or carbon rings or aromatic and / or may contain heteroatoms, chosen from the group consisting of O, N and S, * X represents an H or a cationic entity chosen from the group comprising metal cations;

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

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 carboxylate 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 ^: = RA, of the following formula Vila:

R'iJ *

in which,

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

R'i is a radical chosen from the group consisting of an H, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate,

- RA 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 C10 alkyls, benzyl and the 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.

The term "defined co-polyamino acid" is intended to mean a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula Vllb.

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

0:

OX

© r ₂

Formula Vllb in which m, X, D, Ri and Rz have the definitions given above and at least Ri or Rz is a hydrophobic radical of formula I, V or VI.

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

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula I, V where does he live.

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 Vllb in which Rz is a hydrophobic radical of formula I, V where does he live.

In one embodiment, the composition is characterized in that Ri is a radical chosen from the group consisting of a linear acyl group in Cz to Cio, a branched acyl group in 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 Cz 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, Vila or Vllb in which group D is a group -CHz- (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, Vila or Vllb in which the group D is a group -CH2-CH2- (glutamic unit).

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

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

In one embodiment, the composition is characterized in that the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 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 radical Cx 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 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 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 0.06.

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 the formula V in which the Cx radical comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.15.

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

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.

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

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

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

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

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

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

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

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

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

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

In one embodiment, the composition according to the invention is characterized in that the process for the synthesis of the polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of

N-carboxyanhydride of aspartic acid from which the co-polyamino acid is derived comprises a step of hydrolysis of ester functions.

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

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

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

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

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

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

[WG2- & 64 In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic and chemical depoiymerization of a polyamino acid of higher molecular weight.

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

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

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

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

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

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

In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 40 mg / ml. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 30 mg / ml. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 20 mg / ml [000296] In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 10 mg / mL. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 5 mg / ml.

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

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

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

[000301] The IAPP is treated from a coding sequence of 89 residues. The amyloid Proislet polypeptide (proIAPP, proamyiin, proislet protein) is produced in pancreatic beta cells (beta cells) as a pre-peptide of RSO 67 amino acids, 7404 Dalton, and undergoes post-translational modifications including cleavage of protease to produce amylin.

In this 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 amylin receptor agonist refers to a compound which mimics one or more characteristics of the activity of amylin, [000306] 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 amylin, amylin receptor agonist or amylin analog is amylin.

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 co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog molar ratios 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 molar ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog 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 co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog 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

3.5 and 30, [000316] In one embodiment, the co-polyamino acid / amylin, agonist at the amylin receptor or amylin analog 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 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 molar ratios, agonist at the amylin receptor or amylin analog are between 9 and 30. In one embodiment the co-pelyamino acid / amylin molar ratio , agonist at the amylin receptor or amylin analog is greater than or equal to 1. [000320] In one embodiment, the co-polyamino acid / amylin molar ratios are between 3 and 75.

In one embodiment, the co-polyamino acid / amylin molar ratios are between 7 and 50.

In one embodiment, the co-polyamino acid / amylin molar ratios are between 10 and 30.

In one embodiment, the co-polyamino acid / amylin molar ratios are between 15 and 30.

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

In one embodiment, pramlintide are between 2 and 50.

[000326] 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.

[000329] In one embodiment, pramlintide are between 8 and 30.

In one embodiment, pramlintide are between 10 and 30.

co-polyamino acid molar ratios / co-polyamino acid molar ratios / co-polyamino acid molar ratios / co-polyamino acid molar ratios / co-polyamino acid molar ratios / co-polyamino acid molar ratios / [000331] In one embodiment , the hydrophobic radical radical Hy / amylin, agonist at the amylin receptor or amyine analog are between

1.5 and 150.

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

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

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

2.5 and 60.

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

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

3.5 and 60.

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

[000338] In amylin, agonist 5 and 60.

one in the embodiment, the hydrophobic radical radical Hy / amylin receptor or amylin analog molar ratios are between [000339] In amylin, agonist 7 and 60.

one in the embodiment, the hydrophobic radical Hy / amylin receptor or amylin analogue molar ratios are between [000340] In amylin, agonist 9 and 60.

one in the embodiment, the hydrophobic radical Hy / amylin receptor or analog of amylin molar ratios are between [000341] In amylin is understood an embodiment between, and 60.

the hydrophobic radical Hy / mode molar ratios [000342] In an amylin are between embodiment, and 60.

the hydrophobic radical molar ratios Hy / [000343] In an amylin mode are between embodiment, and 60.

the hydrophobic radical molar ratios Hy / [000344] In a pramiintide mode are between 1.5 and 60.

In one embodiment, the hydrophobic radical molar ratios Hy / [000345] In one embodiment, pramiintide are between 2 and 60.

the hydrophobic radical molar ratios Hy / [000346] In one embodiment, pramiintide are between 3 and 60.

the hydrophobic radical molar ratios Hy / [000347] In one embodiment, pramiintide are between 4 and 60.

the hydrophobic radical radical molar ratios Hy / [000348] In one embodiment, pramiintide are between 5 and 60.

the hydrophobic radical radical molar ratios Hy / [000349] In one embodiment, pramiintide are between 8 and 60.

the hydrophobic radical molar ratios Hy / [000350] In one embodiment, pramiintide are between 10 and 60.

the hydrophobic radical molar ratios Hy / [000351] In one embodiment, the mass ratios 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 at the amylin receptor or amylin analog are between 1.2 and 45.

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

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

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

In one embodiment, the mass ratios of copolyamino acid / amylin, agonist to 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 copolyamino acid / amylin, agonist at the amylin receptor or amylin analog mass ratios 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 at 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, polyamino acid / amylin are between 10 and 27. the ratios mass co-

In one embodiment, pramlintide are between 1.0 and 67.

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.

In one embodiment, the further comprises insulin.

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-poiyamino acid / composition mass ratios is characterized in that it 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 sold under the brands Humulin® (ELI LILLY) and Novolin® (NOVO NORDISK).

[000378] The so-called fast acting prandial insulins are insulins which are obtained by recombination and the primary sequence of which has been modified to reduce their action time.

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

In one embodiment, the meal insulin is insulin lispro.

In one embodiment, the meal insulin is insulin glulisine.

In one embodiment, the mealtime insulin is insulin aspart.

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

[jnsuîinej ...... Pharmacopée.É EP 8., 0, (2014) j Pharmacopée US - USP38 (iÔÏS) J

[.Asparti 1U - 0,0350 mgj'insuhneasp1 | [Lispro, ________ | ... l 0 ..- .. ¾ Q3.47.mg. d ίn su î ineji sp ro ..... [, ÎÛSP, = 0.0347 fflg _: d ^f insuiine iispro ij Human i 1UI ~ 0.0347 mg of insulin [ï USP - 0.0347 mg of insulin ; î ............................. i human ____________________________________________________________________ [. human ............... .................................................. ........... j

Table 40: Units recommended by the pharmacopoeias for insulins [000384] 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 rest of the text U is systematically used interchangeably for the quantities and concentrations of all the insulins, the respective values corresponding in mg are those given above for values expressed in U, LJI or USP, in a embodiment the copolyamino acid / insulin molar ratio is greater than or equal to 1.

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 μΜ (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 μΜ (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 μΜ (iQO at 300 U / mL).

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

[000391] In a fashion of production, she concerns a formulation pharmaceutical characterized in this that the concentration insulin is 600 μΜ (100 U / mL). [000392] In a fashion of production, she concerns a formulation

pharmaceutical characterized in that the insulin concentration is 1200 μΜ (200 U / mL).

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

In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 2400 μΜ (400 U / ml), [000395] In one embodiment, it relates to a pharmaceutical formulation characterized in that ia insulin concentration is 3000 μΜ (500 U / mL).

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

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

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

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

In an embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist receptor amylin or amylin analog molar ratios are between 3 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 3.5 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 an embodiment comprising prandial insulin, the co-polyamino acid / amylin, amylin receptor agonist or amylin analog molar ratios 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 an embodiment comprising prandial insulin, the co-polyamino acid / amyine molar ratios, agonist at the amyiine receptor or amylin analog are between 9 and 30.

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

[000407] In an embodiment comprising prandial insulin, the co-polyamino acid / amyiine molar ratios are between 10 and 50.

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

[000409] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 1.5 and 75.

[000410] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 2 and 50.

[000411] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 3 and 30.

[000412] In an embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 4 and 30.

In one embodiment comprising prandial insulin, the co-polyamino acid / pramlintide molar ratios are between 5 and 30, [000414] In one embodiment comprising prandial insulin, the co- poly molar ratios polyamino acid / pramlintide are between 8 and 30.

[000415] 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 radicals Hy / amyiine, agonist at the amyine receptor or amylin analog are between 1.5 and 150.

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

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

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

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

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

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

[000429] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 1.5 and 60.

[000430] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between? .. and 60.

[000431] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 3 and 60.

[000432] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 4 and 60.

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

[000434] In an embodiment comprising prandial insulin, the hydrophobic radical Hy / pramiintide molar ratios are between 8 and 60.

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

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

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

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

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

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

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

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist at the receptor for amylin or arylin analogue analog ratios are between 2.7 and 27.

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

In one embodiment comprising prandial insulin, the co-polyamino acid / amylin, agonist to receptor for amylin or arylin analogue 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 amyine 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 an embodiment comprising prandial insulin, the co-polyamino acid / amylin mass ratios are between 6.6 and 27.

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

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

In an 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.

In one 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.

[000455] 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.

Furthermore, it is particularly advantageous to combine amylin, an agonist at the amylin receptor or an amine 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 GL.P-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 particularly less than 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, ie 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.

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

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

Said ionic species are chosen from the group of anions, cations and / or zwitterions. By zwitterion is meant a species carrying at least one positive charge and at least one negative charge on two non-adjacent atoms, said ionic species are used alone or as a mixture and preferably as a mixture.

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

In one embodiment, the organic anions comprise less than 1.0 carbon atoms.

In one embodiment, the organic anions are chosen from the group consisting of acetate, citrate and succinate [000484] In one embodiment, the anions are chosen from anions of mineral origin.

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

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

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

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

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

In one embodiment, the cations of mineral origin are chosen from the group consisting of zinc, in particular Zn2 + and alkali metals, in particular Na + and K +, [000491] In one embodiment, the zwitterions are chosen from zwitterions of organic origin.

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

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

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

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

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

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

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

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

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

In one embodiment, the zwitterions of organic origin are chosen from the group consisting of basic or so-called "cationic" amino acids. In one embodiment, the so-called “cationic” amino acids are chosen from arginine, histidine and lysine, in particular arginine and lysine.

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

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

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

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

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

ί

Not a word

ί [000508] In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 10 mM.

[000509] In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 20 mM.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the ionic in the composition is lower or [000526] In one embodiment, the ionic in the composition is lower or [000527] In one embodiment, the ionic in the composition is lower or [000528] In one embodiment, the ionic in the composition is lower or [Ό00529] In one embodiment, the ionic in the composition is lower or [000530] In one embodiment, the ionic in the composition is lower or [000531] In one embodiment, the ionic in the composition is lower or [000532] In one embodiment, the ionic in the composition is lower or [000533] In one embodiment, the ionic in the composition is lower or total molar concentration of species equal to 900 mM.

total molar concentration of species equal to 800 mM.

total molar concentration of species equal to 700 mM.

total molar concentration of species equal to 600 mM.

total molar concentration of species equal to 500 mM, total molar concentration of species equal to 400 mM.

total molar concentration of species equal to 300 mM.

total molar concentration of species equal to 200 mM.

total molar concentration of species equal to 100 mM.

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

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

In one embodiment, the total molar concentration of ionic species in the composition is between 30 and 1000 mM, [000537] In one embodiment, the total molar concentration of ionic species in the composition is between 50 and 1000 mM.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, said ionic species are present in a concentration ranging from 5 to 400 mM.

In one embodiment, said ionic species are present in a concentration ranging from 5 to 300 mM, In one embodiment, said ionic species are present in a concentration ranging from 5 to 200 mM.

In one embodiment, said ionic species are present in a concentration ranging from 5 to 100 mM.

In one embodiment, said ionic species are present in a concentration ranging from 5 to 75 mM.

In one embodiment, said ionic species are present in a concentration ranging from 5 to 50 mM.

In one embodiment, said ionic species are present in a concentration ranging from 5 to 25 mM.

In one embodiment, said ionic species are present in a concentration ranging from 5 to 20 mM.

In one embodiment, said ionic species are present in a concentration ranging from 5 to 10 mM.

In one embodiment, said ionic species are present in a concentration ranging from 10 to 400 mM.

In one embodiment, said ionic species are present in a concentration ranging from 10 to 300 mM.

In one embodiment, a concentration ranging from 10 to 200 mM.

In one embodiment, a concentration ranging from 10 to 100 mM, [000643] In one embodiment, a concentration ranging from 10 to 75 mM.

Said ionic species are present in

Said ionic species are present in

Said ionic species are present in [000644] In one embodiment, said ionic species are present in a concentration ranging from 10 to 50 mM.

In one embodiment, said ionic species are present in a concentration ranging from 10 to 25 mM, [000646] In one embodiment, said ionic species are present in a concentration ranging from 10 to 20 mM.

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

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

In one embodiment, said ionic species are present in a concentration ranging from 20 to 100 mM.

In one embodiment, said ionic species are present in a concentration ranging from 20 to 75 mM.

In one embodiment, said ionic species are present in a concentration ranging from 20 to 50 mM.

In one embodiment, said ionic species are present in a concentration ranging from 20 to 25 mM.

In one embodiment, said ionic species are present in a concentration ranging from 50 to 300 mM.

In one embodiment, said ionic species are present in a concentration ranging from 50 to 200 mM.

In one embodiment, said ionic species are present in an aliant concentration of 50 to 100 mM.

In one embodiment, said ionic species are present in a concentration ranging from 50 to 75 mM.

As regards cations of mineral origin and in particular of Zn ²⁺ , its molar concentration within the composition can be between 0.25 and 20 mM, in particular between 0.25 and 10 mM or between 0.25 and 5 mM.

In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration of between 0 and 500 pM 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 further 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 of between 0 and 200 μΜ per 100 U of insulin.

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

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

In one embodiment, the concentration of preservatives is between 10 and 50 mM.

In one embodiment, the concentration of preservatives is between 10 and 40 mM.

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

In one embodiment, the surfactant is chosen from the group consisting of propylene glycol and polysorbate.

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

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

The compositions according to the invention can also comprise all the excipients in accordance with the pharmacopoeias and compatible with the insulins used at the usual concentrations.

The invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.

In the case of local and systemic releases, the modes of administration envisaged are by the intravenous, subcutaneous, intradermal or intramuscular route. Transdermal, oral, nasal, vaginal, ocular, oral, pulmonary administration 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 analog of arylin 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 analog of arylin, 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 analog of arylin 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 analog of arylin, 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 amonin receptor agonist or an amylin analogue j and a co-polyamino acid according to l 'invention.

The invention also relates to single-dose formulations with a pH of between 6.5 and 7.6 comprising amamyin, an amony receptor agonist 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.

i j [000691] 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 amyiine, of an agonist at the amyiine receptor or of an analogue of amylin, and a polyamino acid carrier of 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.

I 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 amamyin, of a t agonist at the amyiine receptor or of a analogue of amylin, of prandial insulin, and r of a co-polyamino acid carrying carboxylate charges and of at least one hydrophobic radical i according to the invention, in aqueous solution or in lyophilized form. Yes

If necessary, the pH of the preparation is adjusted to a pH of 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 in excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween®) by adding solutions!

[concentrates of these excipients in 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 r the said compositions have a stability measured by Thh greater than that of a [

reference composition comprising amyiine, an amyiine receptor agonist or an amylin analog 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 amamyin, an agonist at the amamyiin 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 amamyin, an agonist at the amamyiin 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 amamyin, an agonist at the amamyiin 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 for stabilizing a composition comprising amamyin, an agonist at the amamyinin receptor or an amylin analog.

The invention also relates to a use of a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals for stabilizing a composition comprising amamyin, an agonist at the amamyin receptor 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 method for stabilizing a composition comprising amamyin, an amonin receptor agonist or an amylin analog or a method for stabilizing a composition comprising amamyin, a receptor agonist amamyin or an amylin analog and a mealtime insulin, and optionally a GLP-1, a GLP-1 analog or a GLP1 receptor agonist.

Description of the figures

HQure..lj.

In this figure is shown graphically the determination of the latency time (LT) by monitoring the fluorescence of Thioflavin T, on a curve having the ordinates ia value of fluorescence (in ua arbitrary units) and on the abscissa time in minutes.

The pharmacokinetic results of pramlintide obtained with the compositions described in examples CA1 / CA2 and CA3 are presented in FIG. 2. Analysis of these profiles indicates that the composition of example CA3 comprising the copolyamino acid BB15, 100 IU / ml of insulin and 0.6 mg / ml of pramlintide (curve drawn with the squares corresponding to example CA3) to obtain a slower absorption of pramlintide than that of the composition of the example in double injection comprising only pramlintide and insulin (curve drawn with the triangles corresponding to the example double injection CA1 / CA2).

Are shown in Figure 3 the pharmacokinetic results of pramlintide obtained with the compositions described in Examples CA1 / CA2 and CA4. Analysis of these profiles indicates that the composition of example CA4 comprising the copolyamino acid AB24, 100 IU / ml of insulin and 0.6 μg / ml of pramlintide (curve drawn with the squares corresponding to example CA4) to obtain a slower absorption of pramlintide than that of the composition of the example in double injection comprising only pramlintide and insulin (curve drawn with the triangles corresponding to the example double injection CA1 / CA2).

The following examples illustrate, without limitation, the invention.

Part A

AA: Synthesis of the hydrophobic intermediate compounds Hy making it possible to obtain the —Hy radicals in which p = 1 [000707] The hydrophobic intermediate compounds are represented in the following table by the corresponding hydrophobic molecule before grafting onto the copolyamino acid.

AA14 . ^rÎi ; “Jmp AA15 _: O ^C '5 ^H 31 HN, .n, χ O, NH ,, χ AM O''''n-Mh' -j _k i; & AA16 I ÎX ‘'i, ,,. <·· ^ i AA17 CH Ο Χ ^ - · Η5 ^Π 31 NH JJ ^h 2 ⁿ Ί] ^NH V \ i 0

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

AAI free: AAI molecule

MoÎéey | e <Al _; ; Product obtained by the reaction between palmitoyl chloride and Lproline.

To a solution of L-proline (10.6 g, 92.1 mmol) in aqueous sodium hydroxide 1 [000709] N (230 mL; 230 mmol) is added dropwise for 90 min a solution 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 37% hydrochloric acid solution are added to obtain a pH = 1. The opalescent reaction medium is then cooled to 0 ° C. The precipitate obtained is filtered on a frit and then washed with water (5 x 50 mL) until filtrates of physiological pH between 6.0 and 8.0 are obtained, then they are dried in an oven at 50 ° C under empty overnight. The product is purified by recrystallization from diisopropyl ether. A white solid is obtained.

Yield: 22.7 g (77%).

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

Mole.r Island A2: Product obtained by reaction between the molecule Al and W-Bocéthyiènediamine.

[000710] 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, N ~ diisopropylethylamine (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 N-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 NaHCCh 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 Ki (CDCb, 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 (1.H); 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 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 (CDCIa, 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 (EST): 396.5; (calculated ([M + H] ⁺ ): 396.4).

Example AA2: AA2 molecule

Molecule A3: 15-rnéthyihexadécan-l-ol.

[000712] 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 remainder of 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 solution of CuCI (482 mg, 4.86 mmol) dissolved in the IMMP (62 mL) at 0 ° C is added dropwise a solution of 12bromo-1- dodecanol (43 g, 162.1 mmol) in THF (60 mL). To this solution is then added dropwise the solution of the warm 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 NazSCU, the solution is filtered and concentrated in vacuo to give an oil. After purification by DCVC on silica gel (cyclohexane, ethyl acetate), an oil which crystallizes at room temperature is obtained.

Yield: 32.8 g (74%)

¹ H NMR (CDCh, ppm): 0.87 (6H); 1.14 (2H) 1.20-1.35 (22H); 1.50-1.55 (3H); 3.64 (2H).

A4 molecule: 15-methylhexadecanoic acid.

To a solution of molecule A3 (20.65 g, 80.5 mmol) and tetrabutylammonium bromide (14.02 g, 42.5 mmol) in a mixture of acetic acid / dichlorethane / water (124/400 / 320 mL) at room temperature is added in small portions of potassium permanganate (38.2 g, 241.5 mmol). After stirring at reflux for 5 h and returning to ambient temperature, the medium is acidified to pH 1 by progressive addition of 5N HCl. NazSCh (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 Na 2 SO 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)

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

Molecule A5: Product obtained by reaction between the molecule A4 and L-proline. [000715] To a solution of molecule A4 (10 g, 37 mmol) in THF (360 mL) at 0 ° C are successively added dicyciohexyl carbodiimide (DCC) (8.01 g, 38.8 mmol) and A / -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-proiine (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 on NazSCki, 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 (EST): 368.3; (calculated ([M + H] ⁺ ): 368.6).

Molecule, A6: Product obtained by reaction between the molecule A5 and / V-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, BocEDA (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 NazSOa, filtered, concentrated in vacuo and the residue is purified by flash chromatography (ethyl acetate, methanol). Yield: 6.9 g (54%)

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

LC / MS (ESI): 510.6; (calculated ([M + HP): 510.8),

Molecule AA2 [000717] A solution of ia 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 h 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 hydrochloride salt.

Yield: 4.6 g (99%)

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

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

Example AA3: AA3 molecule

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

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

Yield: 5.5 g (84%).

NMR * Η (CDCis, 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 AA3 molecule in the form of the hydrochloride salt is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 4.3 g (92%).

MH NMR (DMS0-d6, pprn): 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 (CDCh, 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%).

1 H NMR (CDCb, 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: moüéculs ÂA5

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 ZV-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 (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 (O, 1H); 7.36 (0.9H).

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

AIQ 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%).

³ H 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); 6.33 (0.05H); 7.11 (0.95H).

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

Yield: 292 mg (85%).

³ H NMR (DMSO-d6, ppm): 0.85 (3 H); 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).

Free 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%)

¹ H NMR (CDCI3, ppm): 0.88 (3H); 1.26-1.37 (28H); 1.64-1.70 (2H); 1.88-2.10 (3H);

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

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

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

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 * Η (CDCh, 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 in vacuo 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-ds, ppm): 0.85 (3H); 1.23 (28H); 1.45 (2H); 1.70-2.05 (4H); 2.13 (1H); 2.24 (1H); 2.95 (2H); 3.1.0-3.25 (2H); 3.30-3.65 (10H); 4.20-4.45 (1H); 7.85-8.2.5 (4H).

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

Example AA7: AA7 molecule

Al3 molecule: Product obtained by reaction between arachidic acid and L-proline.

By a process similar to that used for the preparation of the molecule A5 applied to arachidic acid (1.5.51 g, 49.63 mmol) and to L-proline (6 g, 52.11 mmol) in using ia DIPEA in place 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%)

¹ H NMR (CDCh, ppm): 0.88 (3H); 1.28 (34H); 1.66 (2H); 1.95-2.1.5 (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).

frtolécute A14: Product obtained by the reaction between the molecule A13 and Boc-1-amino4,7,10-trioxa-1.3-tridecane amine.

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 (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 + HJ +): 713.1).

Moiécute AA7 [000730] After a process similar to that used for the preparation of the molecule AA2 applied to the molecule A14 (14.25 g, 20.01 mmol), the residue obtained after concentration under vacuum of the reaction medium is dissolved in the methanol and evaporated under reduced pressure, the operation being repeated 4 times to give a white solid of molecule AA7 in the form of the hydrochloride salt.

Yield: 12.7 g (98%)

N 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 + H] ⁺ ): 612.9).

AAS free: AA8 molecule

Molecule A15: 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).

Moiécuie A16: Product obtained by the reaction between the molecule A15 and the methyl ester of L-proline [000732] By a process similar to that used for the preparation of the molecule A2 applied to the molecule A15 (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%)

¹ H NMR (CDCh, ppm): 0.83-1.00 (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).

Molecule Ai7: Product obtained by 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 NazSCh, filtered and then concentrated under reduced pressure to give a colorless oil.

Yield: 4.5 g (80%)

N N NMR (CDCh, ppm): 0.85-0.99 (9H); 1.14-1.41 (24H); 1.43-1.72 (5H); 1.87-2.47 (7H); 3.48-3.55 (0.6H); 3.56-3.62 (0.4ht); 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).

Molecule A.18: Product obtained by the reaction between M-Boc-ethylenediamine and ia molecule A17.

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

Yield: 2.0 g (34%)

NMR M-i (CDCIs, 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%)

Ψ 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: molecule ÂA9

Molecule A1.9: Product obtained by the reaction between iauric acid and L-phenyialanine. 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-phenyialanine (7 g, 42.38 mmol), a white solid is obtained.

Yield: 12.7 g (98%)

NMR (DMSO-ds, 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 ia L-proiine (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 (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).

Molecule A21: Product obtained by saponification of the molecule A2.0.

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 is added lithium hydroxide ( LiOH) (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 (CDCh, ppm): 0.88 (3H); 1.10-1.30 (16H); 1.50-1.80 (3H); 1.67-2.02 (2H); 2.20 (2H); 2.25 (0.4H); 2.60 (0.6H); 2.85-3.10 (2.6H); 3.55-3.65 (1.4H); ; 4.35 (0.6H); 4.55 (0.4H); 4.94 (1H); 6.28 (0.4H); 6.38 (0.6H); 7.20-7.30 (5H).

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

Molecule A22. Product obtained by reaction between / V-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 BocEDA (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 (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 (EST): 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%)

NMR ^! H (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).

Free from AA10: AA10 molecule

Molecule. ... A.23 Product obtained by the reaction between molecule 87 and W-Bocethylenediamine [000741] To a solution of molecule 87 (190.00 g, 583.73 mmol) at 0 ° C in DCM (2, 9 L) are successively added HOBt (8.94 g, 58.37 mmol) and then BocEDA (112.20 g, 700.00 mmol) in solution 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 a saturated aqueous NaHCCh solution (2x1.5 L), a 1N aqueous HCl solution (2x1.5 L) and then a saturated aqueous NaCl solution (1.5 L), dried over NazSCU , filtered and concentrated under reduced pressure. A white solid is obtained after recrystallization from acetonitrile. Yield: 256.50 g (93%)

NMR (CDCh, ppm): 0.88 (3H); 1.16-1.38 (20H); 1.44 (9H); 1.56-1.71 (2H); 1.78-2.45 (6H); 3.11-3.72 (6H); 4.30 (0.1H); 4.51 (0.9H); 4.87 (0.1H); 5.04 (0.9H); 6.87 (0.1H); 7.23 (0.9H).

LC / MS (ESI): 468.0; (calculated ([M + HJ +): 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%)

NMR (MeOD-d4, ppm): 0.90 (3H); 1.2.1-1.43 (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 ξ mslécuîe AA11

Molecule.A24: Product obtained by the reaction between the 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 (CDCia, 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).

AAI molecule 1 [000744] After a process similar to that used for the preparation of the AAI molecule applied to the molecule A24 (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 + Hp): 528.4).

Free AA12: AA12 molecule

Molecule A25: Product obtained by the reaction between the molecule B4 and / V-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 BocEDA (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 [000746] 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 the 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

Moiëcuie A26: Product obtained by coupling between the molecule B1 and / V-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 BocEDA (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 (0.15H); 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 molecule AA13 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] ¹ ): 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 (PtO? _, 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 after 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 [000750] 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 tetrabutylammonium (16.90 g, 52.45 mmol), acetic acetide (150 mL, 2.62 me) then KMnCh (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 solution of 6N HCl (20 mL). NazSCh (53.90 g) is added gradually 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 saturated NaCl solution (200 mL), dried over NazSCh, 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 M (CDCh, 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).

Mo | ecul _: e ₌ A29 _{:. :} Î Product obtained by coupling between the molecule A28 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 NaHCOa (2 x 150 mL), an aqueous solution of 10% HCl (2 x 150 mL), an aqueous solution saturated with NaCI (2 x 150 mL), then drying over NazSO4, filtration and concentration under reduced pressure.

Yield: 23.20 g (95%)

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

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

Molecule .. A3 Q; Product obtained by the saponification of the molecule A29.

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

Yield: 20.40 g (99%)

T1 NMR (DMSO-de, ppm): 0.77-0.91 (15H); 0.97-1.43 (20H); 1.43-1.56 (1H); 1,671.96 (4H); 1.96-2.29 (3H); 3.26-3.56 (2H); 4.20 (0.8H); 4.41 (0.2H).

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

Molecule A31: Product obtained by coupling ia molecule A30 and Boc-1-amino4,7,10-tr! Oxa-13-tridecane amine.

By a process similar to that used for the preparation of the A23 molecule applied to the A30 molecule (8.95 g, 21.85 mmol) and to Boc-l-amlno-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 (0.35H).

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

Meîécute AA14 [000754] After a process similar to that used for the preparation of the AAI molecule applied to the A31 molecule (10.08 g, 1.4.16 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 × 100 mL), dried over NazSCh, 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%)

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

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

Example AA15: AA15 molecule [000755] The AA15 molecule is obtained by the conventional method of peptide synthesis in solid phase (SPPS) on 2-chlorotrityl resin.

To a solution of 4.7.10-trioxa-1.13-tridecanediamine (TOTA, 10.87 mL, 49.60 mmol) in DCM (50 mL) is added DIPEA (8.64 mL , 49.60 mmol). This solution is then poured onto 2-chlorotrityl resin (4.00 g, 1.24 mmol / g) previously washed with DCM in a reactor suitable for SPPS. After 2 h of stirring at room temperature, methanol (0.8 ml / g, 3.2 ml) is added and the medium is stirred for 15 min. The resin is filtered, washed successively with DCM (3 x 50 mL), DMF (2 x 50 mL), DCM (2 x 50 mL), isopropanol (1 x 50 mL) and DCM (3 x 50 mL). The protected amino acids / V-Fmoc-L-giycin and N-Fmoc-L-proline then palmitic acid (3 equivalents) are successively coupled using 1 [bis (dimethylamino) methylene] -lH-1,2, 3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 3 equivalents) as coupling agent in the presence of DIPEA (6 equivalents) in a DCM / DMF 1: 1 mixture. A 20% piperidine solution in DMF is used for the steps of cleavage of the protective group Fmoc. The resin is washed with DCM, DMF and isopropanol after each coupling and deprotection step. The cleavage of the product from the resin is carried out using a TFA / DCM 1: 1 mixture. The solvents are evaporated under reduced pressure, the residue is dissolved in DCM (50 mL) and the organic phase is washed with a 1N aqueous NaOH solution (1 x 50 mL) then a saturated NaCl solution (2 x 50 mL ). After drying on NazSCk, the organic phase is filtered, concentrated under reduced pressure and the residue is purified by chromatography on silica gel (dichloromethane, methanol, NH-iOH). Yield: 1.65 g (54% overall over 7 steps).

NMR (CDCh, ppm): 0.88 (3H); 1.18-2.39 (38H); 2.79 (2H); 3.23-3.44 (2H); 3.47-3.69 (14H); 3.76 (0.92H); 3.82 (0.08H); 3.98 (0.08H); 4.03 (0.92H); 4.34 (0.08H); 4.39 (0.92H); 7.00-7.40 (2H).

LC / MS (ESI): 613.7; (calculated ([MtH] ⁺ ): 613.5).

Example AA16: molecule ΑΑΙδ [000757] By an SPPS process similar to that used for the preparation of the molecule AA15 and using A / -Fmoc-L-phenylalanine (3 equivalents) in place of N-Fmoc- L-glycine, the molecule AA16 is obtained in the form of a yellow oil. Yield: 14.07 g (69%)

¹ H NMR (CDCh, ppm): 0.88 (3H); 1.19-1.34 (24H); 1.41-1.61 (2H); 1.68-2.28 (12H); 2.84 (2H); 3.14 (2H); 3.23-3.67 (16H); 4.19-4.25 (0.1H); 4.38-4.45 (0.9H); 4.59-4.69 (1H); 6.86 (1H); 7.03 (1H); 7.12-7.30 (5H).

LC / MS (ESI): 703.5; (calculated ([M + H] ⁺ ): 703.5).

Example AA17: AA17 molecule By a SPPS process similar to that used for the preparation of the AA15 molecule and using EDA (30.48g, 0.456 mol) instead of TOTA, the AA17 molecule is obtained in the form of 'a solid white.

Yield: 9.19 g (89%)

NMR (MeOD-d4, ppm): 0.90 (3H); 1.22-1.43 (24H); 1.55-1.67 (2H); 1.91-2.04 (2H); 2.04-2.15 (1H); 2.17-2.29 (1H); 2.39 (2H); 2.69-2.82 (2H); 3.25-3.36 (2H); 3.58-3.70 (2H); 3.70-3.97 (2H); 4.25-4.34 (0.9H); 4.44-4.50 (0.1H).

LC / MS (ESI): 453.3; (calculated ([M + H] ⁺ ): 453.4).

AB: Synthesis of co-polyaminoaddes modified by hydrophobic molecules in which p = 1

Statistical co-polyamino acids of formula VII or Vila

CO-POLYAMINOACIDS CARRYING CARBOXYLATE CHARGES AND HYDROPHOBIC RADICALS

NOT· ------- - - * _____

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

Ri = H or pyroglutamate

Hy '' i 0.05, DP (m + n) = 35

Ri = H or pyroglutamate

100

Ri = H or pyroglutamate

101

102

103 abii

We have

H

NOT

Ri

I 'N H

NH ₂ o

NOT

H n

AB 12 ©

Hy i = 0.05, DP (m + n) = .nh ₂

NH

Ri

nl

H

Hy =

Ri = H or pyrogiutamate a 5 ^ ·· “

O

H ₃ C i ™ 0.04, DP (m 4- n) ~

NH / ^C " ^h 31

Hy =

Ri = H or pyrogkitamate

ch,

105

AB22

, .oma

· R,

Ην '' 'Ο ί = 0.16, DP (m + η) - 38' ΝΗ

ΝΗ '' Μ

I ΑΒ23

Ο

Hy = Ο '

R. · = CH3CO or pyroglutamate © "

13 ^π 27 ί = 0.10, DP (m +

Hy

η) -

Γ

ΝΗ

ΝΗ

Ο / 'ÿ ρ Μ q>' ^ 13 ^Π 27

106

107

^X O i = 0.15, DP (m + n) = 39 Hy

Rt = H or pyrogliitamate

108

AB28

AB29

Ο .NH

NH

O

C11H23

Ri n) 40 'C9H19

Hy =

Ri = pyrogSutamate i = 0.15, DP (m + n) = 39

Hy =

Ri = H or pyroglutamate <Qs. “© Me i = 0.15, DP (m

109

110

Table IB List of co-polyamino acids of formula VII or Vila synthesized according to the invention

ill

i = 0.045, DP (m) = 22 Bj „p.y„ .Ryi9.g.Ly.t? tnate .Ohia

Ri = H or pyrog I uta m ate i = 0.038, DP (m) = 26 Ri H or pyroglutamate

I = 0.015, DP (m) 65

Ri - H or pyroglutamate __

WE,.

i

C, H |.

t K · - -γτ vv 'vv' y \ ¹ h ¹ ·· '/

O

I i = 0.017, DP (m) = 60 i R1 = CH3-CO-, H or pyrogiutamate _ __________________________________

112

113

Table IC: List of co-polyamino acids of formula VII or Vllb synthesized according to the invention.

Part AB: Synthesis of the co-po! Yammoacids modified by hydrophobic molecules in which p ™ 1

Co-polyamino acids of formula VII or Vila

Example AB1: Co-polyamino acid ABi - sodium poly-L-giutamate modified by the molecule AAI and having a number-average molar mass (Mn) of 2908 g / mol £ 0J20 [ïâiaLn02 £ hisLABlc.L ^ poly-L- acid glutamic acid of average molar mass in number (Mn) relative 3861 g / mol resulting from the polymerization of y-benzyl-L-glutamate M-carboxyanhydride initiated by hexylamine [000759] In a flask previously dried in an oven is placed under vacuum of 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 in vacuo at 30 ^C C to give a poly (gamma-benzyl-Lglutamique) (PBLG).

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 1 acetic acid (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

114 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 with 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 reaching a pH of 2. 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 compared to a polyoxyethylene (PEG) standard.

Cs-pGYamino acid AB1 [000764] The co-polyamino acid AB1-1 (10.0 g) is dissolved in DMF (700 mL) at 30-40 ° 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., W-methyl morpholine (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 ¹ H NMR in DzO by comparing the integration of the signals from the grafted hydrophobic with that of the signals from the main channel.

115

From the NMR: i = 0.05 [000766] 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, of the aspartate and / or glutamate residues (including a bond amide), the hydrophobic radical, DS and 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-polyamino acid AB2 - sodium poiy-L-glutamate modified by AAI molecule and having a number-average molar mass (Mn) of 3700 g / mol [000767] By a process similar to that used for the preparation of the copolyamino acid AB1 applied to the hydrochloride salt of the molecule AAI (1.64 g, 3.8 mmol) and to a poly-L-glutamic acid with relative Mn 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: 14.1 mg / g

DP (estimated by NMR ^X H): 35

According to NMR = 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-giutamate modified by the AAI molecule and having a number-average molar mass (Mn) of 4900 g / mol [000768] By a process similar to that used for the preparation of the copolyamino acid AB1 applied to the hydrochloride salt of the molecule AAI (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 ABl-1, a sodium poly-L-glutamate modified by the molecule AAI is obtained.

Dry extract: 23.4 mg / g

DP (estimated from ¹ H NMR): 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.

116

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 [000769] By a process similar to that used for the preparation of the copolyamino acid AB1 applied to the hydrochloride salt of the molecule AA2 (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 trimethylsiiane 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

PD (estimated from NMR ’Ή): 35

According to the NMR ^: 1 = 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: Co-polyaminoacs of AB5 - sodium pely-L-glutamate modified by the molecule AA6 and having a number-average molar mass (Mn) of 2600 g / mol [000770] 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 from NMR: 23

According to the 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: € @ -pellyamm © acid AB6 - sodium poly-L-glutamate modified by the molecule AA7 and having a number-average molar mass (Mn) of 4000 g / mol [000771] A poly-L-glutamic acid of average mass Mrs = 3500 g / mol and of 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 30

117 ° C 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 on a 0.2 mm woven filter and poured dropwise onto 3.5 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 rinsed with 100 rnL 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 conductivity 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 NMR: 20

According to NMR 41: i = 0.025 [000772] The calculated average molar mass of the co-polyamino acid AB6 is 3369 g / mol.

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

Example AB7: C © ~ po8yammoacide AB7 - poîy-L-gîutamaie of sodium capped at one of its ends by an acety group and modified by ia molecule AA7 and having a number average molar mass (Mn) of 3300 g / me [000773 ] poly-L-glutamic acid of average molar mass in number (Mn) relative 3600 g / mol and of DP 21 resulting from the polymerization of y-benzyl-L-glutamate / V-carboxyanhydride initiated by i'xyxyine and capped at l 'one of its ends by an acetyl group [000774] 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 hexiamiamine (1.78 g, 17 mmol) is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days and then precipitated in diisopropyiether (3.4 L). The precipitate

118 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 polvigamma-benzyl-L-glutarnic acid) capped at one of its ends by a 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 solution of hydrobromic acid (HBr) at 33 % in acetic acid (235 mL). The mixture is stirred at room temperature for 3 h 30 min, 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 rnL) 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 and then purified by ultrafiltration against a 0.9% NaCl solution, then water to 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 reaching a pH of 2. 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 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

119

PD (estimated from N NMR): 21

According to the NMR: i = 0.03

The calculated average molar mass of the AB7 co-polyamino acid is 3677 g / mol. Aqueous HPLC-SEC (PEG calibrator): Μη = 3300 g / mol.

Example ÂB8: ABS co-polyamide acid - sodium poiy-L-giutamate modified by the molecule AA7 and having a number average molar mass (Mn) of 3600 g / month

Co-polyamino acid ABS -1 poly-L-glutamic acid of number-average molar mass (Mn) 3800 g / mol and of degree of polymerization 24 resulting from the polymerization of y-methyl-L-glutarnate A'-carboxyanhydride initiated by l ammonia [000779] By a process similar to that described in patent application FR-A-2 801 226 applied to γ-methyl-L-glutamic acid M-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.

Co-polyamino acid AB8:

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

DP (estimated from NMR: 24

According to ¹ H NMR: i = 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 ÀB9: Co-polyamino acid AB9 - sodium psiiy-L-giutamate modified by the molecule AA3 and having a number-average molar mass (Mn) of 3200 g / mol [000781] By a process similar to that used for the preparation of the copolyamino acid AB1 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 AA3 molecule is obtained.

Dry extract: 14.7 mg / g

DP (estimated from 1 H NMR): 30

According to the NMR ^: 1 = 0.12

120

The calculated average molar mass of the AB9 co-polyamino acid is 6192 g / mol. Aqueous HPLC-SEC (PEG calibrator): Μη - 3200 g / mol.

Example AB1O: Co-polyamino acid AB1O - sodium poly-L-gtetamate modified by the molecule ÂA4 and having a number-average molar mass (Mn) of 2600 g / mol [000782] 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 from ¹ H NMR): 25

According to the NMR Tl: 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.

Example ABU: Co-polyamino acid ABU ~ poiy-L-sodium glutamate modified by the molecule AA5 and having a number-average molar mass (Mn) of 2700 g / mol [000783] 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 AA5 molecule is obtained.

Dry extract: 20.2 mg / g

DP (estimated from ¹ H NMR): 23

According to the NMR: i = 0.05

The calculated average molar mass of the ABU co-polyarnino acid is 4072 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn ~ 2700 g / month.

Free ABS.2: Co-polyamino acid AB12 - sodium poly-L-gtetamate modified by the molecule AA8 and having a number-average molar mass (Mn) of 3000 g / me [000784] By a process similar to that used for the preparation of copolyamino acid AB1 applied to the hydrochloride of the molecule AA8 and to a poly-L-glutamic acid obtained by a process similar to that used for the preparation of the

121 AB1-1 co-polyamino acid, a sodium poly-L-glutamate modified by the molecule AA8 is obtained.

Dry extract: 19.5 mg / g

DP (estimated by NMR ^X H): 26

According to ¹ H NMR: i = 0.04

The calculated average molar mass of the AB12 co-polyamino acid is 4477 g / month. Aqueous HPLC-SEC (PEG calibrator): Μη == 3000 g / me.

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 [000785] 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 ABl-1 using isoamylamine as initiator in place of hexyiamine, a sodium poly-L-glutamate modified by the molecule AA9 is obtained.

Dry extract: 22.3 mg / g

DP (estimated from ¹ H NMR): 35

According to NMR ^: 1 = 0.12

The calculated average molar mass of the AB13 co-polyamino acid is 7226 g / month. Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / mol.

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 / mass [000786] 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 ABl-1, a sodium poly-L-glutamate modified by the molecule AA7 is obtained.

Dry extract: 22.7 mg / g

DP (estimated from NMR 41): 22

According to NMR '41: 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.

122

Example AB22: Co-polyamino acid AB22 - sodium poly-L-glutamate capped at one of its ends by an acety group and modified by Its molecule AA10 and having a number-average molar mass (Mn) of 4000 g / mol [000787] The hydrochloride salt of the molecule AA10 (4.56 g, 11.29 mmol) is dissolved in chloroform (60 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 through a 0.45 μm filter, the solution is diluted by adding 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 phosphate buffer (150 mM), 0.9% aqueous NaCl solution, then water until the conductivity 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

PD (estimated from T-1 NMR): 38

From ia NMR ^] 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.

Free AB23 ·. Co-polyamino acid AB23 - sodium poly-L-glutamate and modified by the molecule AA10 and having a number-average molar mass (Mn) of 7608 g / mol poly-L-glutamic acid resulting from the polymerization of ybenzyl-L-glutamate / V-carboxyanhydride initiated by hexylamine and capped at one of its ends by a pyroglutamate group

123 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-polyaminamide AB23 [000789] 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

DP (estimated from NMR ^S H): 60

According to ¹ H NMR: 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.

Free 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 [000790] By a process similar to that used for the preparation of 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: 22.9 mg / g

PD (estimated from NMR ^Χ Η): 39

According to NMR: i = 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 / rnol.

Example AB25: Co-polyamino acid AB25 - sodium poly-L-glutamate and modified by the molecule ÂA10 and having a number-average molar mass (Mn) of 4200 g / mol [000791] 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

124 co-polyamino acid AB23-1, a sodium poly-L-giutamate modified by the molecule AA10 is obtained.

Dry extract: 25.9 mg / g

DP (estimated from ¹ H NMR): 39

According to the NMR ⁱ H: i = 0.2

The calculated average molar mass of the co-polyamino acid AB25 is 8509 g / mol. Organic HPLC-SEC (PEG calibrator): Mn ~ 4200 g / mol.

Free AB26: Cs-poiyammoacid AB26 - sodium poiy-L-gtetamate and modified by the molecule A10 and having a number average molar mass (Mn) of 2700 g / m ©!

By a process similar to that used for the preparation of the 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 the co-polyamino acid AB23 -1, a sodium poly-L-glutamate modified by the molecule AA 10 is obtained.

Dry extract: 23.9 mg / g

DP (estimated from NMR · ^ι Η): 22

According to the NMR ^: 1 = 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 poiy-L-gutamate and modified by the molecule AA11 and having a number-average molar mass (Mn) of 4500 g / me [000793] 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 the co-polyamino acid AB23-1, a sodium poly-L-glutamate modified by the AA11 molecule is obtained.

Dry extract: 26.8 mg / g

PD (estimated from ³ N NMR): 39

According to NMR = 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.

125

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 [000794] 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 sodium poly-L-glutamate modified by the AA12 molecule is obtained.

Dry extract: 22.9 mg / g

PD (estimated from NMR ’Ή): 39

According to the NMR ^: 1 = 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-poSyamino acid AB29 - sodium poly-L-glutamate and modified by the molecule AA13 and having a number-average molar mass (Mn) of 4008 g / mol <^ cuojy.âmmoadde_AB29: .l: poly-L acid -glutamic resulting from the polymerization of ybenzyl-L-glutamate / V-carboxyanhydride initiated by hexylamine [000795] In a jacketed reactor, y-benzyl-L-glutamate / Vcarboxyanhydride (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 rnL) is introduced in 1 h 30 min. The reaction mixture is then cooled to 0 ’. This is left stirring for 18 h. The white precipitate is recovered by filtration, washed with diisopropyl ether (2 x 800 ml.) Then dried under reduced pressure at 30 ° C to give a poly (gamma-benzyl-L-giutamic) acid (PBLG).

To a solution of PBL.G (180 g) in / V, / V-dimethylacetamide (DMAc, 450 mL) is added Pd / AbOs (36 g) under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (10 bar) and stirred at 60 ° C for 24 h. After cooling to room temperature and filtration of the catalyst on a sintered P4 and 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, on a 45 min period 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

126

Co-pelyaminsaeide AB29 By a process similar to that used for the preparation of copolyamino acid AB23 applied to the hydrochloride salt of the molecule AA13 and to the copolyamino acid AB29-1, a sodium poly-L-glutamate modified by the molecule AA13 is got.

Dry extract: 16.1 mg / g

PD (estimated from NMR '41): 40

According to the NMR ^! H: i = 0.15

The calculated average molar mass of the AB29 co-polyamino acid is 7734 g / mol. Organic HPLC-SEC (PEG calibrator): Μη = 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 / msl [000798] 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: 29.2 mg / g

DP (estimated from NMR: 40

According to the NMR * H: i = 0.125

The calculated average molar mass of the AB30 co-polyamino acid is 7682 g / mol. Organic HPLC-SEC (PEG calibrator): Mn ~ 4300 g / mol.

Example AB31: Co-polyamino acid AB30 - sodium poly-L-glutamate and modified by the molecule AA1Q and having a number-average molar mass (Mn) of 6300 g / mol [000799] 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 according to NMR: 40

According to NMR ' ^! H: i = 0.175

127

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-gHirtamate and modified by the molecule AA14 and having a number-average molar mass (Mn) of 4700 g / mol [000800] By a process similar to that used for the preparation copolyamino acid AB29 applied to the molecule AA14 and 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 from NMR * H): 40

According to the NMR ^: 1 = 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.

Defined co-polyamino acids of formula VII or Vllb

Free 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 / me [000801] In a suitable container are 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 ÏRN 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) for use directly in the polymerization reaction.

In a balloon previously dried in an oven, γ-benzyi-L-giutamate / Vcarboxyanhydride (25.59 g, 97.2 mmol) is placed under vacuum for 30 min and then anhydrous DMF (140 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of AAI molecule prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to 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

128 solution of hydrobromic acid (HBr) at 33% 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 then is 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 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 'Ή) = 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 [000803] 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 y-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 ¹ H NMR) = 30 therefore i ----- 0.033

The calculated average molar mass of the AB15 co-polyamino acid is 5005 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 4100 g / mol.

Example AB16: Co-palyamino 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 / me [000804] 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

129 mmol) and 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 ^: 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.

Free AB17: Co-polyammoacs of AB17 - sodium poiy-L-gtetamate modified at one of its ends by the molecule AA7 and having a number average molar mass (Mn) of 3500 g / mol [000805] 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 y-benzyl-L-glutamate / V- carboxyanhydride, a sodium polyL-glutamate modified at one of its ends by the molecule AA7 is obtained. Dry extract: 25.2 mg / g

DP (estimated by NMR ^r H) = 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.

Free AB18: Co-polyamino acid ABiS - sodium poiy-L-giutamate modified at one of its ends by the molecule AA7 and having a number-average molar mass (Mn) of 3700 g / mol [000806] 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 ^: Η) = 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.

130

Free AB19: Co-polyamino acid AB19 - sodium poiy-L-gtetamate modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) of 10500 g / mol [000807] 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 y-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 * Η) = 65 therefore i == 0.015

The calculated average molar mass of AB19 co-poiyaminoadde is 10293 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn - 10500 g / mol.

Example AB20: Co-polyamino acid AB20 - sodium poiy-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 [000808] Into a suitable container are successively introduced the hydrochloride salt of the molecule AA6 (0.545 g, 1.00 mmol), chloroform (10 mL), 4 A molecular sieve (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 flask previously dried in an oven, y-benzyl-L-glutamate Ncarboxyanhydride (17.0 g, 64.6 ml) 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 period of 30 min and with stirring. After 1 h of stirring, the precipitate is filtered, washed twice with diisopropyl ether (80 mL) then dried under vacuum at 30 ° C to give a poly (gamma-benzyl-L-glutamic acid) capped at one of its ends by a group

131 acetyl and modified at the other end 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 drop 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 ¹ H NMR) = 60 therefore i = 0.017

The calculated average molar mass of AB20 co-polyamino acid is 9619 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 10400 g / mol.

Example AB33: Co-polyamino acid AB33 - sodium poly-L-glutamate modified at one of its ends by the molecule AA1S and having a number-average molar mass (Mn) of 1800 g / me [000811] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the molecule AA15 (0.82 g, 1.34 mmol) and to 7.75 g (29.4 mmol) of y-benzyl-L-glutamate / V-carboxyanhydride, a solution of sodium poly-Lglutamate modified at one of its ends by the molecule AA15 is obtained. Dry extract: 16.8 mg / g

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

The calculated average molar mass of the co-polyamino acid AB33 is 3897 g / month. Aqueous HPLC-SEC (PEG calibrator): Mn = 1800 g / mol.

132

Example AB34: Co-polyamino acid AB34 - po! YL-sodium giutamate modified at one of its ends by the molecule AA4 and having a number-average molar mass (Mn) of 2600 g / mol [000812] In a flask previously dried at the oven, y-benzyl-L-glutamate / Vcarboxyanhydride (70.9 g, 269.3 mmol) is dissolved in anhydrous DMF (125 mL). The mixture is cooled to 4 ° C., then a solution of AA4 molecule in the form of neutral amine (6.80 g, 12.23 mmol) in DMF (35 mL) is rapidly introduced. The mixture is stirred between 4 ° C and room temperature for 18 h, then heated to 65 ° C for 2 h. The reaction medium is then cooled to room temperature and poured dropwise into diisopropyl ether (2.4 L) with stirring. The white precipitate is recovered by filtration, washed with diisopropyl ether (2 x 125 mL) and then dried under reduced pressure at 30 ° C to give a white solid. The solid is dissolved in / V, / V-dimethylacetamide (DMAc, 150 ml) then Pd / AhCh (6 g) is added under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (10 bar) and stirred at 60 ° C for 24 h. After cooling to room temperature and filtration of the catalyst on a sintered P4 then on a 0.2 μm hydrophilic PTFE Omnipore membrane, a solution of water at pH 2 (900 mL) is poured dropwise onto the DMAc solution, on a 45 min period and with stirring. After 18 h with stirring, the white precipitate is recovered by filtration, washed with water and then dried under reduced pressure at 30 ° C. The solid obtained is dissolved in water (1.25 L) by adjusting the pH to 7 by adding a 1N aqueous sodium hydroxide solution. The pH is then adjusted to pH 12 and the solution is stirred for 1 hr. After neutralization at pH 7, the solution is filtered over 0.2 μm, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, then filtered through an activated carbon filter (3M R53SLP). The solution obtained is filtered over 0.45 μm and purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to around 30 g / L theoretical and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 38.1 mg / g

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

The calculated average molar mass of the AB34 co-polyamino acid is 3991 g / mol. Organic HPLC-SEC (PEG calibrator): Mn = 2600 g / mol.

133

Example AB35: Co-polyamino acid AB35 - sodium poiy-L-glutamate modified at one of its ends by the molecule AA14 and having a number-average molar mass (Mn) of 2500 g / mol [000813] By a process similar to that used for the preparation of copolyamino acid AB34 applied to the molecule AA14 (0.4 g, 0.65 mmol) in solution in chloroform (6.5 mL) and 3.79 g (14.4 mmol) of γ-benzyl -L-glutamate Ncarboxyanhydride in solution in DMF (6.5 mL), and by omitting the step of filtration on activated carbon, a solution of sodium poly-L-glutamate modified at one of its ends by the molecule AA14 is dry extract: 21.0 mg / g

DP (estimated by NMR Ή) = 22 therefore i = 0.045

The calculated average molar mass of AB35 co-polyamino acid is 3896 g / mol. Organic HPLC-SEC (PEG calibrator): Mn = 2600 g / mol.

Example AB36: Co-poiyamino acid AB36 - sodium poly-L-glutamate modified at one of its ends by the molecule AA16 and having a number-average molar mass (Mn) of 2800 g / mol [000814] By a process similar to that used for the preparation of copolyamino acid AB34 applied to the molecule AA16 (3.28 g, 4.67 mmol) and to 27.02 g (102.6 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a solution of sodium poly-Lglutamate modified at one of its ends by the molecule AA16 is obtained. Dry extract: 23.9 mg / g

DP (estimated by NMR Hi) = 22 therefore i = 0.045

The calculated average molar mass of the AB36 co-polyamino acid is 3987 g / mol. Organic HPLC-SEC (PEG calibrator): Mn = 2800 g / month.

Example AB37: Co-polyamino acid AB37 - sodium poly-L-glutamate modified at one of its ends by the molecule AA17 and having a number-average molar mass (Mn) of 2800 g / mol [000815] By a process similar to that used for the preparation of copolyamino acid AB34 applied to the molecule AA17 (4.50 g, 9.73 mmol) and to 56.33 g (214.0 mmol) of y-benzyl-L-glutamate / V-carboxyanhydride, a solution sodium poly-Lglutamate modified at one of its ends by the molecule AA17 is obtained. Dry extract: 26.8 mg / g

DP (estimated by NMR ^X H) - 24 thus i = 0.042

The calculated average molar mass of the AB37 co-polyamino acid is 4049 g / mol. Organic HPLC-SEC (PEG calibrator): Mn = 2800 g / mol.

134

BB: Synthesis of the hydrophobic intermediate compounds Hy making it possible to obtain its -Hy radicals in which p = 2 [000816] The hydrophobic intermediate compounds are represented in the following table by the corresponding hydrophobic intermediate compound before grafting onto the co-polyamino acid.

135 / ^{C 1:27} PM! I '°

^X NH ^C ZZ

ΗΛ

The

NH

LOW

NH

BA6

C | ₅ H ₃₁

NH nq

N., / C ’^ · h ô

NH

NH ^C 15 ^H 31 _, NH

HH <'g

BA7

Z ^ o

N h ₂ i

O

MN

Table ID: List of hydrophobic intermediate compounds synthesized according to the invention.

136

BA: synthesis of hydrophobic intermediate compounds Hy making it possible to obtain the -Hy radicals in which p = 2

BAI example: BAI molecule

Molecule B, 1: Product obtained by the reaction between decanoic acid and L-proline. Dicydohexyl 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 Na2SO <s, filtered, concentrated in vacuo and the residue is purified by chromatography on silica gel (cyclohexane, ethyl acetate).

Yield: 14.6 g (69%)

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

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

Molgij.j.le_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 molecule B1. Applied to the molecule B1 (14.57 g, 54.07 mmol) and to L-lysine (4.15 g, 28.39 mmol ), a yellow oil is obtained.

Yield: 16.4 g (93%)

NMR ^! H (CDCh, ppm): 0.88 (6H); 1,2.6 (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 N-Bocéthyiènediamine.

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-benzotriazoi-l ~ yl ) -1,3,3tetramethyluronium tetratluoroborate (TBTU, 8.52 g, 26.54 mmol) at room temperature. After 30 min of stirring, BocEDA (4.45 g, 27.8 mmol) is added.

137

After stirring at room temperature for 2 h, the solvent is evaporated 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 NaHCOs (250 ml), an aqueous solution of 1 N HCl (250 ml), a saturated aqueous solution of NaCl (250 ml.) And is dried on NazSCh. 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%)

Ή 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 (EST): 791.8; (calculated ([M + H] ⁺ ): 792.1).

BAI molecule [000820] To a solution of molecule B3 (12.78 g, 16.15 mmol) in dichloromethane (110 mL) at 5 ° C is added a solution of 4N HCl in dioxane (20.2 mL } After 20 h of stirring at 5 ° C., the medium is concentrated in vacuo The residue obtained is dissolved in methanol and evaporated in vacuo, this operation being repeated 4 times to give a white solid of BAI molecule in the form of sei hydrochloride Yield: 11.4 g (97%)

NMR (DMSO-d ₆ , 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%)

4-1 NMR (CDCh, ppm): 0.87 (3H); 1.26 (16H); 1.70 (2H); 1.90-2.10 (3H); 2.35 (2H); 2.49 (1H); 3.48 (1H); 3.56 (1H); 4.60 (1H).

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

138

Molecule B 5: Product obtained by the reaction between the molecule B4 and L-lysine. By a process similar to that used for the preparation of the B1 molecule applied to the B4 molecule (33.72 g, 113.36 mmol) and to L-lysine (8.70 g, 59.51 mmol) , a white solid is obtained.

Yield: 26.2 g (66%)

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).

Molecule B6 ......; product obtained by reaction between N-Boc-ethylenediamine and the molecule

B5.

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

Yield: 30.9 g (quantitative)

¹ H NMR (CDG ;, 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 BA2 molecule in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 27.65 g (97%)

NMR (DMSO-de, ppm): 0.85 (6H); 1.10-2.40 (54H); 2.75-3.1.5 (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).

BA3 free: BAS molecule

Molecule B7: Product obtained by the reaction between myristic acid and ia 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 ia L-proline (10 g, 86.86 mmol), a yellowish oil is obtained.

Yield: 20 g (78%)

139

‘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).

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

Moiêçule.BS ,: Product obtained by the reaction between the molecule B7 and L-lysine [000826] 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 W-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 BocEDA (3.03 g, 18.92 mmol), a crude oil is obtained after purification by a chromatographic column on silica gel (ethyl acetate, methanol).

Yield: 12.5 g [88%)

‘H NMR (DMSO-d6, 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).

Moiécuie BA3 [000828] After a process similar to that used for the preparation of the BAI molecule applied to the B9 molecule (12.5 g, 13.84 mmol), the residue obtained after concentration under vacuum is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of BA3 molecule in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 9.2 g (79%)

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

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

J 140 ΐ

ri

Example BA4: BA4 molecule

B1.0 molecule; Product obtained by the reaction between the molecule B8 and Boc-1-amino4,7,10-trioxa-13-tridecane amine.

[000829] By a process similar to that used for the preparation of the molecule

I B3 applied to the molecule B8 (29.80 g, 39.15 mmol) and to Boc-1-amino-4,7,10-trioxa13-tridecane amine (15.05 g, 46.96 mmol), an oil colorless thick is obtained. Yield: 25.3 g (61%) { ¹ H NMR (DMSO-de, ppm): 0.85 (6H); 1.25-2.35 (75H); 2.85-3.20 (6H); 3.25-3.65 (16H); 4.10-4.45 (3H); 6.38 (0.1H); 6.72 (0.9H); 7.50-8.25 (3H).

LC / MS (ESI): 1064.2; (calculated ([M + H] ⁺ ): 1064.5).

ΐ

BA4 molecule After a process similar to that used for the preparation of the BAI j molecule applied to the B10 molecule (25.3 g, 23.8 mmol), the residue obtained after j concentration in vacuo is dissolved in methanol and evaporated in vacuo, 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%)

I ^'X H 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).

I

Example BA5: SA5 molecule j

Molecule Ml,: Product obtained by reaction between the molecule Al and ia L-Lysine [000831] 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 ί 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 ohase is acidified to pH 1 by slow addition of 6N HCl. The product is extracted 3 times with dichloromethane, the organic phase is dried over j NazSOi then filtered and concentrated under reduced pressure to give 11.2 g of residue i

oily yellow. 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%)

141

NMR ^: H (CDCh, ppm): 0.87 (6H); 1.06-2.44 (70H); 2.78-2.96 (1H); 3.35-3.75 (5H); 4.28-4.43 (O, 1H); 4.43-4.52 (0.2H); 4.52-4.61 (1.8H); 4.61-4.75 (0.9H); 7,748.02 (2H).

LC / MS (ESI): 818.0; (calculated ([M + H] ⁺ ): 818.7).

Molecule B12: Product obtained by coupling between the molecule Bll and N-Bocethylenediamine [000832] By a process similar to that used for the preparation of the molecule B3 applied to the molecule Bll (18.00 g, 22.02 mmol) in solution in THF and with BocEDA (4.23 g, 26.43 mmol), a white solid is obtained after recrystallization twice from acetonitrile.

Yield: 17.5 g (83%)

Ή 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).

BASE [000833] 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 under vacuum 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.

Yield: 1.4.28 g (65%)

1 H NMR (DMSO-d6, ppm): 0.85 (6H); 1.06-2.32 (70H); 2.53-2.63 (2H); 2.89-3.61 (10H); 4.04-4.43 (3H); 7.55-7.62 (0.65H); 7.65-7.72 (0.65H); 7.80 (0.65H); 7.91 (0.35H) 8.03 (0.35H); 8.14-8.23 (0.35H).

LC / MS (ESI): 860.0; (calculated ([M + H] ⁺ ): 860.8).

142

Example BA6: BA6 molecule

Molecule B13: Product obtained by the reaction between / V- (tert-butoxycarbonyl) -1,6diaminohexane and ia 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 solid bianc is obtained after recrystallization from acetonitrile.

Yield: 10.7 g (85%)

NMR 41 (CDCh, ppm): 0.88 (6H); 1.17-2.40 (79H); 3.00-3.71 (10H); 4.26-4.58 (3H); 4.67 (1H); 6.74 (1H); 7.34-7.49 (2H).

LC / MS (ESI): 959.9; (calculated ([M + H] ⁺ ): 959.8).

BAS 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 in the reaction medium 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 on NazSCU, the organic phase is filtered, concentrated in vacuo and the residue is recrystallized from acetonitrile.

Yield: 5.4 g (58%)

NMR (CDCh, ppm): 0.88 (6H); 1.19-2.40 (72H); 2.67 (2H); 3.03-3.70 (8H); 4.26-4.57 (3H); 6.71 (1H); 7.39-7.49 (2H).

LC / MS (ESI): 859.8; (calculated ([M + H] ⁺ ): 859.7).

Example BA7: BA7 molecule

Molecule B14: Product obtained by coupling between the molecule B7 and 2,3diaminopropionic acid [000836] 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%)

H NMR ^J (DMSO-U6, 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).

143

Molecule ......... Bl5: product obtained by coupling between the molecule B14 and N-Bocethylenediamine [000837] 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 BocEDA (8.56 g, 53.40 mmol), a colorless oil is obtained after purification by chromatography on silica gel (ethyl acetate, methanol) . Yield: 24.5 g (64%)

NMR (DMSO-d6, ppm): 0.85 (6H); 1.16-2.42 (65H); 2.89-3.14 (4H); 3.17-3.66 (6H); 4.11-4.43 (3H); 6.77 (1H); 7.38-8.23 (3H).

LC / MS (ESI): 861.7; (calculated ([M + H] ⁺ ): 861.7).

MoiécuSe BA7 [000838] 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 NazSO4, filtered and concentrated under reduced pressure. A white solid is obtained after recrystallization from acetonitrile.

Yield: 19.7 g (91%)

NMR (DMSO-d6, ppm): 0.85 (6H); 1.10-2.40 (58H); 2.51-2.62 (2H); 2.90-3.16 (2H); 3.16-3.67 (6H); 4.04-4.47 (3H); 7.33-8.27 (3H).

LC / MS (ESI): 761.5; (calculated ([M + H] ⁺ ): 761.6).

144

BB: Synthesis of o-polyammoacids modified by hydrophobic molecules in which p ™ 2

Co-polyamino acids of formula VI or Vila

CO-POLYAMISMOACIDES CARBOXYLATE CHARGE CARRIERS ΕτΊ OF HYDROPHOBIC RADICALS I

Ri = H or pyroglutamate

145

BB2

j = 0.047, DP (m + n) = / 5 /

^{0 C} 11 ^H 23

^X NH.-¾.

"Π V MMH% π

Hy = O

Ri = H or pyroglutamate _ ____

146

147

148

149

RI- CH3-C0-, H or pyrogkitamate

150

151

152

153

154

155

156

Table IE List of co-polyamino acids of formula VII or VII synthesized according to the invention in which p = 2

157

Co-poiyamineacsdes of formate VII su Vllb

N ’CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER AND

HYDROPHOBIC RADICALS

BB15 i = 0.034, DP (m) = 29

Ri H or pyroqlutamate cua

i = 0.045, DP (m) = 22

Ri = H or pyroglutamate

158

BB15

r {t r J f i = 0.043, DP (m) = 23 | Ri = H or pyroglutamate

BB18

BB17

i = 0.015, DP (m) = 65 Ri ~ H or pyrogjutamate

i = 0.025, DP (m) - 40 Rl = H or pyroglutamate

159

Fbbis ft .Ofc

R

Hy · * i ~ 0.045, DP (m + n) - 60 / —- · <

l H ^C 13 ^H 27

O ο '' NH j BB20 ', .0'

N- .. Z

Hy =

Ri = pyrogiutamate

Γνη

ΓΝΗ ’m

NH

^{C 3:31} p.m.

"NH

Ο, NH

NaO ' ^x 0 i = 0.043, DP (m) = 23

R ~ Houpyrogiutamate

160

BB21

! v

Ο c ₁₃ h ₂₇ i = 0.11, DP (m) = 9 4, R1 = H or pyroglutamate BB22 ......................... .........................

NaO 'O i = 0.04, DP (m) = 25 _____4 Rl = H or pyroglutamate

BB23T ”~’ HJXT

HH

C ₁₃ H ₂₇

Ο

RI

C ₁₃ H ₂₇

NaO Ό i = 0.048, DP (m) = 21

R.l = H or pyroglutamate

161

162

Table IF: List of co-polyamino acids of formula VII or Vllb synthesized according to the invention.

BB: Synthesis of co-poiyamino acids modified by hydrophobic molecules in which p = 2.

Example BB1: Co-poHyamino acid BB1 - sodium poly-L-giutamate modified by the molecule BA2 and having a number-average molar mass (Mn) of 2400 g / mol

Cmeolyâmii ^^ poly-L-glutamic acid of average molar mass in number (Mn) relative 3860 g / mol resulting from the polymerization of y-benzyl-L-glutamate / V-carboxyanhydride initiated by hexylamine [000839] In a balloon previously dried in an oven is placed under vacuum of ybenzyl-L-glutamate / V-carboxyanhydride (90.0 g, 342 mmol) for 30 min, then

163

Anhydrous DMF (465 mL) is introduced. The mixture is then stirred under argon until complete dissolution, cooled to 4 ° C., then hexiamiamine (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 55 ° 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 polyCy-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 hydrobornic acid (HBr) at 33% in l acetic acid (135 mL, 0.77 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 (1.6 L). After 1.5 hours 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 dissolved 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 perrneum 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 with a number-average molar mass (Mn) 3860 g / mol relative to a polyoxyethylene (PEG) standard.

Co-polyamino acid BBÎ [000844] The co-polyamino acid BBl-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 BA2 molecule (2.95 g, 3.8 mmol) is suspended in DMF (45 mL) and triethylamine (0.39 g, 3.8 mmol) is then added to this. suspension then the mixture is slightly heated with stirring until complete dissolution. In 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.

164 reaction 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 on 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 from ¹ H NMR): 23

According to ¹ H 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 Îa molecule BA2 and having a number-average molar mass (Mn) of 4900 g / mo [000845] 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 molecule BA2 (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 ie DMF, to NMM (3.7 g, 36.7 mmol), the solution of molecule BA2 then to 2-hydroxypyridine / V-oxide (HOPO, 0.31 g, 2, 76 mmol) are added successively. The reaction medium 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 dropwise onto 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 up 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

165 perimetral conductimetry 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 from NMR ’Ή): 21

According to the NMR ^! 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 S400 g / mol

Co-oolvaminoacMg SB3-1; 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 [000846] A poly-L- acid glutamic acid in number average mass (Mn) 17,500 g / mol relative to a standard polymethyl methacrylate (PMMA) is obtained by polymerization of γ-methyl / V-carboxyanhydride of glutamic acid using Lieucinamide as initiator and carrying out deprotection 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-poiyaminoacie BB3-1 (11 g), a poly -Sodium glutamate modified by the BA2 molecule is obtained.

Dry extract: 27.5 mg / g

DP (estimated from NMR ^] H): 34

According to the NMR: 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 - poSy-L-sodium giutamate modified by the molecule BA2 and having a number-average molar mass (Mn) of 10500 g / mol [000848] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to the hydrochloride of the molecule BA2 (5 g, 6.35 mmol) and to a poly-L-glutamic acid of average molar mass in number Mn = 10800 g / mol (21.7 g) obtained by a process similar to that used for the preparation

166 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 from ⁵ H NMR): 65

According to the NMR Ή: 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 BBS: Co-polyamino acid BBS ~ 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 3600 g / mol ÇûU2SiMân; dilQaclde ... ... BB5.J. 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 an acetyl group [000849] In a flask previously dried in the oven is placed under vacuum of γbenzyl-L-glutamate / V-carboxyanhydride (100.0 g, 380 mmol) for 30 min 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 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-benzyi-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 acetic acid (235 mL, 1.34 mol). The mixture is stirred at room temperature for 3 h 30 min, 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 dissolved in water (1.5 L) by adjusting the pH to 7 by adding an aqueous sodium hydroxide solution 10

167

N 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 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 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-giutamic acid of number average molar mass (Mn) 3700 g / mol compared to a polyoxyethylene (PEG) standard.

Co-polyamino acid BBS 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 ^J H): 23

According to the NMR Ή: 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.

Free BB6: Co-polyamino acid BBe - 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 [000852] 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 the 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 from NMR: 24

According to the NMR ^: 1 = 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 / month.

168

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 [000853] 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 / me (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

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 BÀ2 and having a number-average molar mass (Mrs) of 5200 g / m ©!

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 number-average molar mass Mn = 4100 g / mol (5.0 g) obtained by a process similar to that used for the preparation of copolyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BA2 is obtained.

Dry extract: 28.6 mg / g

PD (estimated from NMR ^] Ή): 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 BAS molecule and having a number-average molar mass (Mn) of 4700 g / mol [000855] 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 ΒΒ1-Ί, 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

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 / month.

Example BB1O: co-polyamino acid BB1G - sodium poly-L-glutamate modified by the molecule BA3 and having a number-average molar mass (Mn) of 4200 g / mol [000856] By a process similar to that used for the preparation of the copolyamino acid BB2 applied to se! hydrochloride 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 copolyamino acid BB1-1, a sodium poly-L-glutamate modified by the molecule BA3 is obtained.

Dry extract: 25.9 mg / g

DP (estimated by NMR ^X H): 22

According to ¹ H NMR: 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 BBîl: co-polyamino acid BBÎÎ - sodium poly-L-glutamate capped at one of its ends by an acetyte group and modified by the molecule BA4 and having a number-average molar mass (Mn) of 39ΘΘ g / mol [000857] 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 according to ³ H NMR): 22

According to the NMR ^X H: i = 0.032

The calculated average molar mass of the co-polyamino acid BB11 is 4118 g / mol.

170

Aqueous HPLC-SEC (PEG calibrator): Mn = 3900 g / mol.

Example BB12: co-polyamino acid BB12 - sodium poiy-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 [000858] By a process similar to that used for the preparation of copolyamino acid BB2 applied to se! hydrochloride of the molecule BA3 (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-glutarnate 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 from ia NMR Ή): 23

According to the NMR ^: 1 = 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 p-ïy-L-giutamate modified by the BAI molecule and having a number-average molar mass (Mn) of 2800 g / mol [000859] 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 process similar to that used for the preparation of co-polyamino acid BB1-1, a sodium poly-L-glutamate modified by the BAI molecule is obtained.

Dry extract: 25.6 mg / g

PD (estimated from NMR ^Τ Η): 25

According to ¹ H NMR: 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.

Free BB14: co-polyamino acid BB14 - sodium poly-L-gtetamate modified at one of its ends by the BAS molecule and having a number-average molar mass (Mn) of 402 © g / mol [000860] In a suitable container are successively introduced the hydrochloride salt of the molecule BA2 (2.12 g, 2.70 mmol), chloroform (40 mL), sieve

171 molecular 4 Å (1.5 g), as well as Amberlite IRN 150 ion exchange resin (1.5 g). After 1 hour of stirring on rollers, the medium is filtered and the resin is. rinsed with chloroform. The mixture is evaporated and then co-evaporated with toluene. The residue is dissolved in anhydrous DMF (20 mL) to be used directly in the polymerization reaction.

In a balloon previously dried in an oven, y-benzyl-L-glutamate Ncarboxyanhydride (18 g, 68.42 mmol) is placed under vacuum for 30 min and then anhydrous DMF (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 and 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 °. vs. 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 uS / 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: 22.3 mg / g

DP (estimated by ¹ H NMR) = 29 therefore 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.

172

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 [000862] 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 y-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 ’Ή) = 24 so 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 [000863] By a process similar to that used for the preparation of copolyamino acid BB14 applied to se! hydrochloride of the BA4 molecule (5.70 g, 5.70 mmol) and 29.99 g (113.9 mmol) of y-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 M) = 23 therefore i ~ 0.043

The calculated average molar mass of co-poiyaminoadde BB16 is 4399 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / moL

Example BB17: co-polyamino acid BB17 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass of 10700 g / mol [000864] 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.

173

Example BB18: co-polyamino acid BB18 - sodium poSy-L-giutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass of 6600 g / mol [000865] By a process similar to that used for the preparation of the copolyaminoadde BB14 applied to the hydrochloride salt of the molecule BA3 (2.51 g, 3 mmol) and to 31.6 g (120 mmol) of y-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 41) = 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.

Free 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 [000866] By a process similar to that used for the preparation copolyamino acid AB23 applied to the hydrochloride salt of the molecule BA3 and copolyamino acid AB23-1, a sodium poly-L-glutamate modified by the molecule BA3 is obtained,

Dry extract: 25.3 mg / g

DP (estimated according to ¹ H NMR): 60

According to ¹ H NMR: 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 BB20 - sodium pely-L-glutamate modified at one of its ends by the molecule BA5 and having a number-average molar mass (Mn) of 2800 g / mol [000867] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the molecule BA5 in the form of free amine (1.70 g, 1.98 mmol) and of y-benzyl-L-glutamate / V-carboxyanhydride (11.46 g, 43, 5 mmol), a sodium polyL-glutamate modified at one of its ends by the molecule BA5 is obtained. Dry extract: 20.7 mg / g

DP (estimated by ¹ H NMR) = 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.

174

Example BB21: co-polyamino acid BB21 - sodium poly-L-glutamate modified at one of its ends by the molecule BAS and having a number-average molar mass (Mn) of 1100 g / mol [000868] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the BA3 molecule in the form of free amine (3.814 g, 4.75 mmol) and of y-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 Ή) = 9 therefore i - 0.11

The calculated average molar mass of the co-polyamino acid BB21 is 2123 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 1100 g / mol.

Free BB22: co-polyaminoacid® BB22 ~ sodium poly-L-glutamate modified at one of its ends by the molecule ΒΑδ and having a number-average molar mass (Mn) of 3300 g / mol [000869] 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 arnine (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 Ψ) = 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 psIy-L-glutamate modified at one of its ends by the molecule BA7 and having an average molecular mass ers number (Mn) of 2900 g / mol [000870] 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 y-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 ‘H) = 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.

175

Example BB24: cs-polyamino acid BB24 - sodium poly-L-giytamate modified at one of its ends by the molecule BA3 and modified by the molecule BAS and having a number-average molar mass (Mn) of 2300 g / me [ 000871] Co-polyamino acid BB24-1; poly-L-glutamic acid modified at one of its ends by the BA3 molecule 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 (13.66 g, 105.8 mmol), HOBt (2.35 g, 15.3 mmol) and EDC (20 , 28 g, 105.8 mmol). After 24 h of stirring at 25 ° C., the solution is concentrated under vacuum to remove the chloroform and 50% of the DMF. The reaction mixture is then heated to 55 ° C. and 1150 ml of methanol are introduced over 1 hour. The reaction mixture is then cooled to 0 ° C. After 18 h, the white precipitate is recovered by filtration, washed three times with 270 ml. diisopropyl ether then dried under vacuum at 30 ° C to obtain a white solid, The solid is diluted in TFA (390 mL), and a solution of hydrobromic acid (HBr) at 33% 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 around 30 g / L theoretical, filtered through 0.2 μm and then acidified to pH 2 with stirring by addition of a 37% HCl solution. The precipitate is then recovered by filtration, washed twice with water and then dried under vacuum at 30 ° C to obtain a white solid.

176

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 the 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 according to the NMR Ti): 22

According to ¹ H NMR: 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: œ-poiyamino acid BB25 - sodium poiy-L-gfetamate modified at one of its ends by the molecule BA3 and at the other end by te meecute BS and having a number-average molar mass (Mn) of 2000 g / mol [000874] DCC (0.257 g, 1.24 mmol) and NHS (0.143 g, 1.24 mmol) are introduced into a solution of molecule B8 (0.946 g, 1.24 mmol) in the DMF (8 mL) ). After 16 h of stirring at room temperature, the solution is filtered to be used directly in the following reaction.

In a balloon previously dried in an oven, y-benzyl-L-glutamate AAcarboxyanhydride (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 kings 15 mL) then dried under vacuum at 30 ° C to give a white solid. The solid is diluted in TFA (23 mL), then the solution is cooled to 4 ° C. A 33% HBr solution in acetic acid (15 mL, 85.7 mmol) is then added dropwise. The mixture is stirred at room temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (0.28 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed twice with a 1: 1 (v / v) mixture of diisopropyl ether and water (24 mL) then twice with water (24 mL). The solid obtained

177 is then dissolved in water (0.16 L) by adjusting the pH to 12 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After 30 min the pH is adjusted to 7 by slow addition of an aqueous solution of HO 1 N. 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 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: 18.9 mg / g

PD (estimated from N NMR): 22

According to the NMR ^Χ Η: k == 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.

C. COMPOSITIONS

Example CV1: Preparation of a 0.6 mg / mL human arylin solution containing m-cresoi (29 mM), glycerin (174 mM) at pH 7.4.

[000876] A solution of human arylin concentrated at 3 mg / ml is prepared by dissolving human arylin 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 CV2: Preparation of a 0.6 mg / mL human arylin solution containing co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 7.4.

[000877] 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 humannyline solution at 3 mg / ml as described in example CV1 is added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to obtain the final compositions CV5 to CV11 (table 1g). The final pH is adjusted to 7.4 by adding NaOH / HCl.

178

_; Solution Ratio BB15 / human amylin BB15 copolyamino acid concentration Visual aspect of the solution mol / mol i mg / mL mM CVI : limpid CV5 5 7 3 ' 0.73 limpid CV6 6 3.6 0.S8 limpid CV7 7 1.03 limpid CV8 8 ....... .......... 4.8 .1.17 limpid CV9 9 M ............... .............. 1.32 limpid CV.1.0 10 6 1.47 limpid CV11 17 10.5 2.57 limpid

Table lg: Compositions and visual appearance of human amylin solutions at pH 7.4 at different concentrations of co-polyamino acid BB15.

Example CY1: Preparation of a 0.9 mg / ml pramlintide solution containing m-cresoi (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 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 CW1: Preparation of a pramlintide solution at û, 4 mg / ml containing phenol (30 mM), ia glycerin (174 mM) and ia glycylglycine (8 mM) at pH 7.4.

By a method similar to that used in Example CY1, a pramlintide solution at 0.4 mg / ml. containing phenol (30 mM), glycerin (174 mM) and glycylglycine (8 mM) at pH 7.4 is obtained.

Example C ¥ 0: Preparation of a pramlintide solution at 0.9 mg / ml containing co-polyamino acid SB15, m-cresol (29 mM) and glycerine (174 mM) 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) to a concentrated solution of co-polyamino acid BB15, [000882] A solution of concentrated pramlintide 5 mg / mL is added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to obtain the final compositions CY2 to CY7 (Table 3). The final pH is adjusted to 7.4 by adding NaOH / HCl.

179

Solution Ratio BB15 / pramlintide BB15 copolyamino acid concentration Visual aspect of ia r solution i mol / mol mg / mL mM CY1 7 - limpid CY2 2 i ........................ U ........................ ............. 0.44 limpid CY3 3 i ............ 2.7 ........................... f 0.66 limpid CY4 4 'J 3.6 0.88 limpid CY5 5 ............. 4.5 1.10 limpid CY6 6 i 5.4, 1.32 limpid CY7 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 CWO: Preparation of a pramlintide solution at 0.4 mg / ml containing co-polyamino acid BB15, phenol (30 mM), glycerin (174 mM) and glycylgiycin (S mM) at pH 7, 4.

By a protocol similar to that used in Example CY0, from a pramlintide solution at 0.4 mg / mL CW1, 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 CW2 and CW3 are obtained.

Solution Co-polyamino acid BB15 concentration Ratio BB15 / pramlintide Visual aspect of the solution mg / ml mM mol / mol CW2 2.4 0.59 6 limpid CW 3 4 0.98 10 limpid

Table 4: Compositions and visual appearance of pramlintide solutions at 0.4 mg / ml at pH

7.4 at different concentrations of co-polyamino acid BB15.

CPO example: Preparation of a 0.9 mg / mL pramlintide solution 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 CY0, solutions of pramlintide at 0.9 mg / ml containing different co-polyaminoaddes of the invention, mresol (29 mM) and glycerin (174 mM ) at pH 7.4 CP2 to CP12 are obtained.

180

Solution Co- i poly · ami _: noac ide Concentration in copolyamino Ratio co- i polyamino acid / pra mlintide Visual aspect of the solution mg / m The mM mol / mol CP2 BB1 5 5 10 1.22 2.45 5.4 10.8 limpid i crystal clear CP3 BB1 4 5 10 0.98 1.96 4.3 8.6 limpid limpid CP4 AB1 7 5 10 1.11 ........................ 1.22 4.9 9.8 limpid limpid CP5 AB1 5 5 10 0.99 1.99 4.4 i 8.8 limpid limpid CP6 AB1 4 5 10 1.48 2.96 6.5 13 limpid limpid CP10 BB1  8: 5 10 0.72 1.44 3.2 6.3 limpid limpid CP11 BB9 5 10 1 2.01 4.4 i 8.8 limpid limpid CP12 BB2 5 10 1.27 2.54 5.6 11.2 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.

Example CH1: Preparation of a pramlintide solution at 0.6 mg / ml containing m-cresol (29 mM) and glycerin (174 mM) at pH 6.6.

A pramlintide solution concentrated at 5 rng / rnL 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 CHO: Preparation of a pramlintide solution at 0.6 mg / ml containing co-polyamino acid BB15, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6.

[000886] 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. at pH 4 is added to this concentrated solution of co-polyamino acid BB15 and of excipients so as to

181 obtain the final compositions CH2 to CH8 (Table 9). The final pH is adjusted to 6.6 by adding NaOH / HCl.

Solution Ratio BB15 / pramiintide BB15 copolyamino acid concentration Visual aspect of the solution i mol / rnoi ; mg / mL  mM CH1 ) “; - limpid CH2 2 1.3 0.29 limpid CH3 3 2 0.45 limpid CH4 4 2.7; | 0.61. limpid CH5 6 4 0.90 limpid CH6 8 5.3 1.19 limpid CH7 10 6.7 <1.50  limpid 1 CH8 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,

Example IOC: Preparation of a 0.6 mg / ml pramlmtide solution containing various o-po! Yamin © acids of the invention, m-cresol (29 mM) and glycerin (174 mM) at pH 6 6.

By a protocol similar to that described in Example CHO, solutions of pramlintide at 0.6 mg / ml containing different co-polyamino acids of the invention, mresol (29 mM) and ia glycerin (174 mM ) at pH 6.6, C11 to CI.14 and CI15 are obtained.

182

Solution copolyamino Concentration • in co- . polyamino Ratio co- polyamino / pramlintide Aspect visual < from the 1 solution mg / mL mM mol / I CH BB20 1.3 I 1 2.6 0.3 0.6 2 4 Crystal clear i limpid IC2. BB21 1.3 0.6 4 limpid CI3 AB22 2.4 0.3 2 limpid CI4 BB24 2.9 0.6 J 4 limpid CI5 BB25 • 1.5 '3 0.3 0.6 2 4 limpid limpid IC6 AB23 3.4 0.23 2 limpid IC7 AB28 2.3 • 4.7 0.3 0.6: · 2 4 limpid limpid IC8 AB24 1.2 2.4: 0.15 0.3 · ' 1 2 limpid limpid CI9 AB25 1.3 2.6 0.15; 0.3: 1 2 limpid limpid IC10 AB26 0.7 1.5 i 0.15 0.3 1 i 2 | limpid limpid cm AB27 1.3 2.7: 0.15 0.3 1 2 limpid limpid CI12 AB31 1.3 ; 2.5 1 0.15 0.3 1 2 limpid limpid IC13 AB29 8.9 1.15 7.6 limpid Cïi4 AB32 1.3 1 2.5 0.15 _: 0.3 1 : 2 i limpid limpid CI15 AB17 : 5.3 1.2 8 limpid

Table 10: Compositions and visual appearance of pramlintide solutions at pH 6.6 in the presence of different co-polyamino acids.

183

Example CTO: Preparation of a 0.6 mg / mL pramlintide solution containing AB14 co-polyammoacid, m-cresoï (29 mM), glycerin (174 mM) NaCl and zinc chloride at pH 6 , 6 [000889] A concentrated solution of co-polyamino acid AB14 and of excipients is prepared by adding concentrated solutions of excipients (rn-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 CTI to CT5 (Table 11). The final pH is adjusted to 6.6 by adding NaOH / HCl.

Solution: Co- polyamino Co-polyamino acid concentration [NaCl] [ZnCbJ Aspect : visual: r of the : solution: mg / mL: mM .................................................. .. (MM) (MM) CTI AB 14 6.3: 1.87 ; 0.75 limpid CT2 AB14 6.3 : 1.87 50 limpid CT3 AB14 6.3 | 1.87 100 limpid CT4 AB 14 6.3 1.87 50 0.75 limpid CT5 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.

CSG-free: Preparation of a pramlintide solution at 0.6 mg / mL containing various œ-polyamino acids of the invention, m-cresol (29 mM), glycerin (174 mM), NaCl and zinc chloride at pH 6.6 [000891] By a protocol similar to that described in Example CTO, solutions of pramlintide at 0.6 mg / ml containing various co-polyamino acids of the invention, rnresol (29 mM) and glycerin (174 mM), sodium chloride and zinc chloride at pH 6.6 CS1 to CS11 and CS12 to CS24 are obtained.

184

Solution Co- polyamino Concentration in co-polyamino acid [NaCl] [ZnCI ₂ ] Aspect  visual of the  solution mg / mL mM (mM) i (MM) CS1 AB15 7.8 1.6 : limpid CS? A.B15 11..7 2.3 - • Clear i CS3 AB15 3.9 0.8 50 : : Clear CS4 AB 15 6.3 1.3 50 i limpid CS5 AB15 ; 7.8: : 1.6 J 50 i limpid CS6 AB.1.5 3.9 : 0.8 100 i “ limpid CS7 AB16 12.4 : l _f 5; * l - Ç limpid CS8 AB 16 16.7 2.1 · " limpid CS9 ABÏ6: ; 7.4: : 0.9 i 50 : Clear i CS10 AB16 12.4 1.5 50 limpid CSU AB16 7.4 0.9 50 1 limpid

Table 12: Compositions and visual appearance of pramlintide solutions at pH 6.6 in the presence of different co-polyamino acids and of different contents of sodium chloride and zinc chloride.

Self uti we Co- polyaminoac ide Concentratio n in co- polyaminoac ide Ratio co- poiyaminoacide / prarnl intide [NaC n [ZnCl 2] Visual aspect : of the: soluti i on; mg / j mL mM me / mol (mM ’) (MM) CS12 AB16 12.4 1.6: 10.5 : 25 " . Limpi i from J CS13 AB 16 ; 12.4 1.6 10.5 25 1 Limpi j from: CS14 AB16 10 1.3 8.4 50 Limpi: from i

185

Soluti we Copoiyaminoac ide Concentration in copolyaminoac ide Ratio co-: polyamino acid / praml i intide: [NaC 1] [ZnCl 2] Visual aspect of the . soluti ' we mg / ml mM mol / mol i • (mM ) (MM) CS15 AB16 10 1.3 8.4 100 Limpi of CS16 AB34 6.1 1.5 10: > Limpi from CS17 1 AB34 6.1 1.5 io: . 100 _: Limpi de ' CS18 AB34 6.1 1.5 10: 100 1 ? Limpi from CS 119 AB33 5.7 1.5 10 Limpi from CS20 AB33 5.7 1.5 10 50 CS21 'ÂB33 5.7 1.5 10 50 : 1 Limpi from _: CS22 : AB33 5.7 1.5 10 100 Limpi. of CS23 AB33 5.7 1.5 10 i 100 1 Limpi's CS24 AB36 9.5 2.4 15.7 Limpi of CS25 AB36 5.1 1.3 8 _: 50 Limpi from CS 2 6 AB35 5.9 1.5 10 : Limpi's CS 2 7 AB35 ' 3.6 ' 0.91 6 25 Limpi i of

Table 12a: Compositions and visual appearance of pramiintide solutions at pH 6.6 in the presence of different co-polyamino acids and different contents of sodium chloride and zinc chloride.

186

Example CXI: Preparation of a 0.6 mg / ml human amylin solution and 100 IU / ml human insulin 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 CV1 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 Arnphastar. 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 CX2: Preparation of a 0.6 mg / mL human amylin solution and 100 IU / mL human insulin containing co-polyamino acid BB15, mcresoi (29 mM), glycerin (174 mM) and zinc chloride (229 pM) at pH 7.4.

[000893] 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 CXI, CX6, CX10 and CX11 solutions are prepared according to the above protocol.

Solution Ratio BB15 / human amylin Co-concentration i polyamino acid BB15 Visual aspect of the solution mol / mol mg / ml mM CX1 ï - turbid CX6 6 3.6 0.88 limpid CX10 10 6 , 1.47 limpid CX11 '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 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.

187

CHI-free: Preparation of a 0.4 mg / mL pramlintide solution and 100 IU / mL human insulin containing phenol (30 mM), glycerin (174 mM), glycylglycine (8 mM) and zinc chloride (229 μΜ) at pH 7.4. A concentrated pramlintide solution at 5 mg / mL is added to a concentrated solution of excipients (m-cresol, glycerin, glycylgiycin, 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.

CRI example: Preparation of a pramlintide solution 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.

By a process similar to that used in Example CN1, 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 NOC: 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), 8a glycylgiycin (8 mM) and zinc chloride (229 pM) at pH 7.4.

[000899] A concentrated solution of co-polyamino acid BB15 and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, glycylgiycin, 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. excipients so as to obtain the final composition targeted (Table 14). The final pH is adjusted to 7.4 by adding NaOH / HCl.

The CN2 and CN3 solutions are prepared according to the above protocol.

Solution Copolyamino acid concentration BB15 Ratio BB15 / pramlintide Visual appearance of the mixture mg / mL mM mol / mol CN1 turbid CN2 ....... U * 0.59 6 limpid CN3 4 0.98 10 limpid

Table 14: Compositions and visual appearance of the pramlintide solutions at 0.4 mg / ml and human insulin at 100 IU / ml at pH 7.4 at different concentrations of BB15 copolyarninoadde.

188 [000902] In the presence of the co-polyamino acid BBlb, a clear solution of pramlintide (0.4 mg / mL) and human insulin (100 IU / mL) is obtained at pH 7.4.

Free from CRO: Preparation of a pramlintide solution at 0.9 mg / mL and human insulin at 100 IU / mL containing co-polyamino acid BB15, mcrésoî (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 7.4.

By a process similar to that used in Example CN0, 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 CR2 to CR4 and CU2 to CU8 are prepared according to the above protocol.

Solution Copolyamino acid concentration BB15 Ratio BB15 / pramlintide mol / mol Visual aspect of the solution mg / mL mM SHOUT turbid CR2 2.7 0.66 | 3 limpid CR3 3.6 _r 0.88 _; 4 limpid CR4 4.5 1.10 5 Limp: to CU2 0.9 0.22 1 limpid CU 3 1.8 0.44 2 limpid CU7 5.4 1.32 6 limpid CU8 9 2.20 1.0 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.

[000905] 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.

189

CGO free: Preparation of a pramlintide solution at 0.9 mg / mL and human insulin at 100 IU / mL containing different co-polyamino acids of the invention, m-creso! (29 mM), glycerin (174 mM) and zinc chloride (229 pM) at pH 7.4.

By a process similar to the CNO 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-cresoi (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 7.4 is obtained.

The solutions CG2 to CG12 are prepared according to the protocol described above.

Solution copolyamino Concentration in co- polyamino Ratio Co- polyamino / prarnlintide Visual aspect of the solution mg / mL mM mol / mol CG2 BB15 5 10 1.22 2.45 5.4 10.8 limpid limpid CG3 BB14 5 10 0.98 1.96 4.3 8.6 limpid CG4 AB17 5 10 1.11 1.22 4.9 9.8 limpid limpid CG5 AB 15 5 10 0.99 1.99 4.4 8.8 limpid CG6 AB14 5 10 1.48 2.96 G _f 5 13 · clear CG 10 BB18 5 10 0.72 1.44 3.2 1 6.3 limpid limpid CG 11 BB9 I 5 10 1 2.01 4.4 1 8.8 limpid limpid CG12 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.

190

CD1 free: Preparation of a pramlintide solution at 0.9 mg / mL and insulin lispro at 100 IU / mL containing m-cresoi (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.

Example CD0: Preparation of a pramlintide solution at 0.9 mg / mL and insulin lispro at 100 IU / mL containing co-polyamino acid BB15, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (300 μΜ) at pH 7.4.

[000909] 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 final targeted composition. The final pH is adjusted to pH 7.4 by adding NaOH / HCl.

The solutions CD3 to CD9 are prepared according to the protocol described above.

Solution Ratio BB15 / pramlintide Concentration of copolyamino acid BB15 / Visual aspect of the solution mol / mol mg / ml mM CD1 i Turbid CD3 2 1.8 0.44 limpid CD4 3 2.7 0.66 limpid CD5 4 3.6 0.88 limpid CD6 5 4AE L-AiL-l limpid CD7 6 5.4 1.32 limpid CD8 10 i 9 2.20 limpid CD9 15 13.5 1330 limpid

Table 17: Compositions and visual appearance of the solutions of pramlintide at 0.9 mg / ml and insulin Iispro 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 Iispro insulin (100 IU / ml) at pH 7.4 is obtained.

191

Example CK1: 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 pM) at pH 6.6.

By a process similar to that used in the CRI example, a solution of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL containing m-cresol (29 mM), ia glycerin (174 mM) and zinc chloride (229 pM) at pH 6.6 is obtained.

Example CK0: 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.

By a process similar to that used in Example CR0, a solution of pramlintide at 0.6 rng / 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 CK2 to CK8 are prepared according to the above protocol.

• Solution Ratio BB15 / pramlintide Co-concentration . polyamino acid BB15 Visual aspect of the solution me / mol ; mg / ml mM CK1  - i turbid CK2 2 1.3 0.29 limpid CK3 3 2 0.45 limpid 1 CK4 4 2.7 0.61 limpid CK5 6 4 ; 0.90 limpid CK 6 8 5.3 1.19 limpid CK7 10 6.7 1.50 limpid CK8 15 10 ^ 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 at pH 6.6 at different concentrations of copolyamino acid BB15.

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 CFI: Preparation of compositions containing variable concentrations of pramlintide, human insulin at 100 IU / mL, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6.

By a process similar to that used in the CRI example, solutions containing different concentrations of pramlintide, human insulin at 100 IU / mL,

192 m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH

6.6 are obtained.

Solution Concentration pramlintide (mg / ml.); Visual aspect of the solution CFI A 03 turbid CF1B 0.8 turbid CF1C <0.6 turbid CFI D 0.3 turbid CF1Ë 03 turbid i

Table 18a: Compositions and visual appearance of the solutions of pramlintide at different concentrations and of human insulin at 100 IU / mL at pH 6.6.

Example CFO: Preparation of compositions containing variable concentrations of pramlintide and human insulin at 100 IU / mL in the presence of co-polyamino acid AB24, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6. By a process similar to that used in Example CR0, solutions containing different concentrations of pramlintide, human insulin at 100 IU / mL, co-polyamino acid AB24, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 pM) at pH 6.6 are obtained.

Solution • Pramlintide concentration Co-concentration _: polyamino acid i 'AB24 Copolyamino acid / pramlintide ratio Visual aspect of the solution · (Mg / ml.) mg / ml mM mol / mol CF2 0.9 5.4 0.67 3 limpid CF 3 i 0.8 4.8 0.6 3 limpid CF4 0.6 3.6 0.45 3 limpid CF5 l 0.3 1.8 0.22 3 limpid CF6 0.2 1 0,125 ................... 35 limpid

Table 18b: Compositions and visual appearance of the solutions of pramlintide at different concentrations and of human insulin at 100 IU / ml in the presence of co-polyamino acid AB24 at pH 6.6.

193

Free from CMO: Preparation of a solution of pramlintide at 0.6 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 pM) at pH 6.6.

By a process similar to the CGO example, 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.

The solutions CM1 to CM 18 are prepared according to the protocol described above.

Solution Co- polyamino Concentration as copolyamino acid I Ratio : co ~ polyamino / pramlintide Visual aspect] of the solution mg / MI ? mM i mol / mol CM1 BB20 2.6 i 5.3 : 0.61: 1.22 4 8 limpid limpid CM2 BB2.1 0.6 4 limpid CM3 AB22 2.4 0.3 2 limpid CM4 BB24 ..... AA ... 0.6 : 4 limpid CM 5 BB23 3 0.76: 5 limpid CM6 BB25 1.5 : 0 _t 3: 2 Limoide CM7 BB22 2.7 0.6 4 limpid CM8 AB23 AA ... 0.69 <5 limpid CM9 BB19 4.7 0.4 2.8 limpid CM10 AB28 ..AT? 0.3 2 Limoide CM11 AB24 1.2 2.4 i 3.6 0.15 0.3 0.45 1 2 i- 3 limpid Clear: CM 12 AB25 aa 0.3 2 limpid CM13 AB26 1.5 2.3 0.3 i 0.5 i 2 i 3 limpid limpid CM14 AB27 1.3 2.7 1 0.15 0.3 : 1 2 limpid Crystal clear i CM 15 AB30 1.2 „AL 0.15 0.3 : 1 > 2 Clear: limpid CM16 AB31 1.3 ' 2.5 0.15 i 0.3 J : 1 : 2 limpid limpid CM17 AB29 5.9 . 8.9 J 0.8 1.15 : 5 7..6 limpid limpid CM18 AB 3 2 AA. . „„ „P, 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 co-polyamino acids.

194

Free CQ1: Preparation of a solution of pramlintide at 0.6 mg / ml and human insuiine at 100 l / 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) [000921] A concentrated solution of AB14 co-polyamino acid and of excipients is prepared by adding concentrated solutions of excipients (rn -cresol, glycerin, sodium chloride, zinc chloride) to a concentrated solution of AB14 co-polyamino acid.

A concentrated pramlintide solution at 5 mg / ml at pH 4 and then a solution of human insulin at 500 lU / 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 solution CQ1 is prepared according to the above protocol.

Example CQQ: Preparation of a solution of pramlintide at 0.6 mg / mL and human insulin at 100 lu / mL containing various co-polyamino acids of the invention, rnresol (29 mM), glycerin (174 mM ), and different contents of sodium chloride and zinc chloride [000924] By a process similar to example CQO, solutions of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL containing different co-polyamino acid of the invention, m-cresol (29 mM), glycerin (174 mM), sodium chloride and zinc chloride at pH 6.6 are obtained.

The solutions CQ2 to CQ12 are prepared according to the above protocol.

195

Solution Co- polyamino Co-polyamino acid concentration [NaCl] • [ZnClz]: Aspect visual | of the: solution mg / mL mM (MM) i (mM): CQ1 AB 14 6.3 1 1.87 100 _: 1 limpid CQ2 AB15 7.8 1.6 - 0.23 limpid CQ3 ABI5 J V : 2.3 .......... - * 0.23 limpid AB.15 3.9 L 0.8 50 0.23 limpid CQ5 AB 15 <6.3 i 1.3 50 0.23 limpid CQ6 AB15 , ............................ 7 J d L 1.6 50 0.73 limpid C27 q AB15 . 3.9 .......... i 0.8 100 0.23 limpid CQ8 AB15 6.3 1.3 100 0.23 limpid ÇQLi AB15 7.8 1.6 100 0.23 limpid CQ10 AB16 . 7-4 0.9 50 0.23 limpid CQ11 AB16  12.4 1.5 50 0.23 limpid CQ12 AB16 7 4 „ δ · ~ ..... : 50 1> limpid

Table 20: Compositions and visual appearance of the solutions of pramlintide at 0.6 mg / mL and human insulin at 100 ILJ / mL pH 6.6 in the presence of different co-polyamino acids and of different sodium chloride and chloride contents zinc.

Example CZO: Preparation of a 0.6 mg / ml pramlintide solution containing DMPG, m-cresol (29 mM), glycerin (174 mM) at pH 6.6.

[000926] A concentrated solution of DMPG and of excipients is prepared by adding concentrated solutions of excipients (m-cresoi, 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.

196

Example CZ1: Preparation of a 0.6 mg / mL pramiintide solution containing DMPG (4.5 mM), phenol (30 mM), Sa glycerin (174 mM) and glycylglycine (8 mM) at pH 7.4.

Solution DMPG (MM) Pramiintide concentration ..ÏTJ / rnU pH excipients Visual aspect of the • solution i CZ0 4.5 0.6 6.6 m-crésoi 29 mM Glycerin 174 mM limpid CZ1 4.5 0 6 7.4 phenol 30 mM glycylgiycin 8m M glycerin 174 mM limpid

Table 21: Compositions and visual appearance of pramiintide solutions at 0.6 mg / mL in the presence of DM PG.

Example CAI: Preparation of a pramiintide solution at 1 mg / ml containing m-cresol (20 mM), mannitol (43 mg / ml), and a sodium acetate buffer, at pH 4.

A concentrated solution of pramiintide at 10 mg / ml is added to a concentrated solution of excipients (m-cresol, mannitol, sodium acetate) so as to obtain the intended final composition. The final pH is adjusted to 4 by adding NaOH / HCl. The clear solution is filtered (0.22 μm) and introduced into 3 ml glass cartridges for pen injector.

Example CA2: Cartridge of a commercial solution of human insulin at 100 IU / mL (Humulin *) containing m-cresol (23 mM), glycerin (174 mM) and zinc chloride (230 μΜ) .

A commercial solution of Humulin® in vial of 10 ml is taken and introduced into glass cartridges of 3 ml for pen injector.

Example CA3: Preparation of a 0.6 mg / ml pramiintide solution and 100 IU / ml human insulin containing co-polyamino acid BB15 (3.1 mg / ml), m-cresol (20 mM) , glycerin (35 mM), mannitol (2.6% w / v), tris (18.75 mM), sodium acetate (18 mM), and zinc chloride (260 pM ) at pH 6.2.

3 mL glass vials are filled with 0.5 mL of a solution containing 10 mg / mL of BB15 co-polyamino acid and 60 mM tris at pH 8.3. The solution

197 is lyophilized so as to obtain vials of 3 ml containing 5 mg of copolyamino acid BB15 and 30 pmol of tris.

A 500 IU / mL solution of human insulin containing 23 mM of mcresol, 174 mM of glycerin and 260 μΜ of zinc chloride at pH 7.4 is prepared by adding concentrated solutions of excipients (m-cresol , glycerin, zinc chloride) to a concentrated solution of concentrated human insulin at 760 IU / mL.

[000932] In the vial containing 5 mg of co-polyamino acid BB15 and 30 pmol of sorting are introduced successively:

0.96 mL of the Pramiintide solution at 1 mg / mL at pH 4 described in Example CAI;

0.32 mL of sterile water for injection;

0.32 ml. human insulin concentrated to 500 IU / mL containing 23 mM of mcresol, 174 mM of glycerin and 260 μΜ of zinc chloride at pH 7.4.

The clear solution is filtered (0.22 μm) and introduced into 3 ml glass cartridges for injector pen.

Example CA4: Cartridge filling of a pramiintide solution at 0.6 mg / mL and human insulin at 100 IU / mL in the presence of co-polyamino acid AB24 at 2.4 mg / mL, of m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6.

The solution of pramiintide at 0.6 mg / mL and human insulin at 100 IU / mL in the presence of co-polyamino acid AB24 at 2.4 mg / mL, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6 described in example CM11 is filtered (0.22 μΜ) and introduced into 3 ml glass cartridges for pen injector.

Example CA5 (pump stability): Preparation of a pramiintide solution at 0.6 mg / mL and insulin lispro at 100 IU / mL at pH 6.6 containing copolyamino acid AB24, m-cresol (29 mM) , glycerin (174 mM) and zinc chloride (300 pM).

A concentrated solution of AB24 co-polyamino acid and of excipients is prepared by adding concentrated solutions of excipients (m-cresol, glycerin, zinc chloride) to a concentrated solution of AB24 co-polyamino acid.

A concentrated pramiintide solution at 10 mg / mL and then a solution of insulin lispro at 200 IU / mL are added to this concentrated solution of copolyamino acid AB24 and of excipients so as to obtain the final targeted composition. The final pH is adjusted to 6.6 by adding NaOH / HCl.

198

CASE Example: 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 [000937] 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 human insulin solution at 800 HJ / 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 CA7: Preparation of a solution of pramlintide at 0.6 mg / mL and human insulin at 100 XU / mL containing co-polyamino acid BB15 (10 mg / mL), m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 pM) at pH 6.6 [000939] 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 final composition targeted. The final pH is adjusted to 6.6 by adding NaOH / HCl. The clear solution is filtered (0.22 pM) and introduced into 3 ml glass cartridges

D. PHYSICO-CHEMISTRY

D I: Results of visual observations of the mixture and fibrillation measurements per ThT

Principle [000941] The poor stability of a peptide can lead to the formation of amyloid fibrils, defined as ordered macromoiecular 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

199 having a characteristic fluorescence signature when binds to amyloid-like fibrils (Naiki et al. (1989) Anal. BioChem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 2.74-284).

This method makes it possible to follow the formation of fibrils for low concentrations of ThT in undiluted solutions. This monitoring is carried out under accelerated stability conditions: with stirring and at 37 ° C.

Experimental conditions [000944] The samples were prepared just before the start of the measurement. The preparation of each composition is described in the associated example. Thioflavin T was added to the composition from a concentrated stock solution so as to 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 μM in the case of human amylin compositions at 0.5 mg / mL, 2 μΜ in the case of pramlintide compositions at 0.9 mg / mL and 0.6 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.

[000945] A volume of 150 μL of the composition was introduced into a well of a 96-well plate. Each composition was analyzed in three trials (triplicate) within the same plate. The plate was sealed with transparent film to avoid evaporation of the composition.

This plate was then placed in the enclosure of a plate reader (EnVision 2104 Multilabel, Perkin Elmer or Xenius XM, Safas). The temperature is adjusted to 37 ° C., and lateral agitation of 960 rpm with 1 mm of amplitude is imposed.

[000947] 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.

[000949] 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 reported latency time value corresponds to the average of the latency time measurements made on three wells.

200 [000950] An example of graphical determination is shown in Figure 1.

DI free: Stability of human amylin solutions at 0.6 mg / mL at pH 7.4 in the presence of co-polyamino acid 8815 at different concentrations.

Solution BB15 / amylin ratio _: human i Concentration in copolyamino acid BB15 Latency (h) mol / mol mg / ml; mM CV1 - - <0.02 CV5 5 3 0.73 > 1 CV6 6 3.6 0.88 > 5 CV7 7 4.2 1.03 > 30 CV8 8 ... AE8 ..... 1.4Z ....... ...... > 54 CV9 9 5.4 1.32 > 54 CV10 10 6 > 72

Table 22: Measurement of the latency time by ThT (40 pM) of solutions CV1 to CV10.

The latency time of a human amylin solution at pH 7.4 (CV1), devoid of co-polyamino acid, is less than 0.02 h; CV5 to CV10 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 h.

201

Example D2: Stability of solutions of human amylin at 0.6 mg / ml and of human insulin 100 IU at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio BB15 / amylin human ' Co-polyamino acid BB15 concentration Latency (h) mol / mol mg / mL rn M CX1 * CX6 6 3.6 0.38 > 0.1 CX10 10 6 Z 1.47 > 0.5 CX11 17.5 10.5 2.57 > 5

* Latency time not measured because turbid solution

Table 23: Measurement of the latency time by ThT (40 μΜ) of the solutions, CX6, CX10 and

CX11.

The solution of human amylin and human insulin at pH 7.4 (CX1) is turbid. The co-polyamino acid BB15 makes it possible to obtain a clear solution containing human amyiine in the presence of human insulin at pH 7.4 with latency times greater than 0.1 hour from a molar ratio BB15 / amyiine human of 6, and greater than 5 h for a molar ratio BB15 / human amyiin of 17.5.

Example D3: Stability of pramlintide solutions at 0.4 mg / ml at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution i BB15 copolyamino acid concentration Z Ratio 1 Bbls / pramlintide Latency (h) mg / ml  mM mo! / mol CWI - : 0.7 CW2 2.4 0.59 6 > 40 CW3 • 4 0.98 10 > 63

Table 24: Measurement of the latency time by ThT (1 μΜ) of solutions CW1 to CW3.

The pramlintide solution at pH 7.4 (CW1) devoid of co-polyamino acid has a short latency time. The co-polyamino acid BB15 makes it possible to obtain a solution containing pramlintide at pH 7.4 with latency times greater than 40 h from a BB15 / pramlintide molar ratio of 6,

202

Example D4: Stability of pramlintide solutions at 0.9 mg / ml. at pH 7.4 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio BB15 / pramlintide BB15 concentration Latency (h) mol / mol ;. mg / ml ............... mM CY1  ........ ...... 0.7 .....: CY2 2 1.8 0.44 .................> 0.8 ........... CY3 3 2J ......... 0.66 > 4 CY4 4 3.6 0.88 > 30 CY5 5 4.5 1.10 > 63 CY6 6 1.22 > 63 CY7 10 ____________ 9 1.32 > 63

Table 25: Measurement of the latency time by THh (2 μΜ) of the solutions CY1 to CY7 [000954] The pramlintide solution at pH 7.4 (CY1) devoid of co-polyamino acid has a short latency time; the latency times of the solutions containing a co-poiyamino 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.

Example D5: Stability of solutions of pramlintide at 0.9 mg / ml at pH 7.4 in the presence of different co-polyamino acids.

Soiutio π Copolyaminoacid e Concentration in co- 1 polyamino acid Ratio co- polyamino / pramlintid e Time of 1 latency _: e (h); mg / m L. mM mol / mol CY1 ; - : 0.7 i CP2 BB15 5 10 1.22 2.45 : 5.4 10.8 m r) Λ Λ CP3 BB14 10 1.96 8.6 > 15 CP4 AB17 10 1.22 9.8 > 63 CP10 BB18 • 10 0.72 1.44 3.2 6.3 > 63 > 63 1 CP11 BB9 5 10 i 1 2.01 4.4 8.8 > 50 > 63 CP12 BB2 5 1 10 i 1.27 2.54 5.6 1 ........ -............ 1Χ2 > 10 > 63

Table 26: Measurement of the latency time by Thh (2 μΜ) of the compositions CY1, CP2 to

CP12.

203 The pramlintide solution at pH 7.4 (CY1) 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 10 h under the conditions tested.

Example D6: Stability of pramlintide solutions at 0.6 mg / ml. at pH 6.6 in the presence of co-polyamino acid BB15 at different concentrations.

Solution Ratio Bbls / pramlintide BB15 copolyamino acid concentration Latency (H) me me . mg / mL m M CH1 - 1 CH 2 2  . IA. ........ .Q3? > 4; CH 3 3 2 0.45 > 10 CH4 4 2.7 0.61 > 50 CH 5 6 4 0.90 > 50 CH 6 8 5.3 1.19 > 50 CH7 10 6.7 1.50 > 50 CH 8 15 10 2J4 " > 50

Table 27: Measurement of the latency time by ThT (2 μΜ) of the solutions CH1 and CH2 to

CH8.

The pramlintide solution at pH 6.6 (CH1) devoid of co-polyamino acid has a short latency time; the latency times of the solutions containing a co-polyamino acid are greater than the latency times of the composition without copolyamino acid.

Example D7: Stability of pramiintide solutions at 0.6 mg / mi at pH 6.6 in the presence of different co-polyamino acids.

Solution copolyamino Concentration in co- i polyamino acid Ratio co- polyamino / pramlintide Latency (h) mg / mL : mM mol / mol Eyelash BB20 1.3 / 2.6 he 0.3 0.6 2 4 > 10 > 20 IC2 BB21 . .13 .. 0.6 4 > 10 Cl 3 AB22 2.4  0.3 2 > 10 CI4 BB24 2.9 0.6 4 > 10 CI5 BB25 1.5 3 0.3  0.6 2 4 > 50 > 50 CI 6 AB23 3.4 0.23 2 > 10 IC7 AB28 2.3 I ............ 1.7 .................... 0.3 0.6 2 4 > 10 > 10 IC8 AB24 1.2 2.4 ...... 0.15 i 0.3 1 2 > 10 > 50 CI9 AB25 1.3 2.6 0.15 0.3 1 2 > 10 > 10

204

'Solution Co- / polyamino acid Concentration in copolyamino acid Ratio co-> polvaminoacid / pramlintide 1 Latency time i (h) _; mg / mL mM · mol / mol i IC10 AB26 1.5. 0.3 2 > 10 cm AB27 1.3 2.7. . 0.15 0.3 ' 1 2 > 5 > 10 CI12 AB31 1.3 2.5 0.15 0.3 1 2 > 10 > 10 : CI 13 AB29 8.9 1.15 7.6 > 5 1 CI14 AB32 1.3 0.15 0.3 1 i 2 i > 10 '> 10

Table 28: Measurement of the latency time by Thh (2 μΜ) of the compositions C11 to IC14, [000957] The pramlintide solution at pH 6.6 (CH1) devoid of co-polyamino acid exhibits a short latency time. The co-polyamino acids of the invention make it possible to obtain latency times greater than 5 h under the conditions tested.

Example D7A: Stability of solutions of pramlintide 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 copolyamino Concentration in co-polyamino acid [NaCl] [ZnCl] Latency (H) mg / mL mM 1 (mM) / (MM) CP6 AB14 10 2.96 - ... <2 CTI AB14 6.3 1.87 “I 0.75 0.6 CT2 AB14 6.3 1.87 50 : > 2 CT3 1 AB14 6.3 1.87 100 > 5 CT4 AB14 6.3 1.87  50 0.75 > 5 CT5 AB14 6.3 1.87 100 0.75 > 20

Table 29: Measurement of the latency time by THh (2 μΜ) of the CTI compositions at CT5 [000958] The solution of pramlintide at pH 6.6 and of co-polyamino acid AB14 exhibits a longer latency time in the presence of sodium chloride or sodium chloride and zinc.

20.5

Example D7B: Stability of pramiintide 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 acid i Concentration in co-polyamino acid [NaCl] [ZnCi ₂ ] Latency (H) mg / mL mM (MM) (MM) CS1 i AB15 | 7.8 1.6 · j * - 3.5 CS 2 1 AB15 11.7 1 2.3 " - > 30 CS3 AB15 3.9. 0.8 50 > 10 CS4 AB 15 6.3 .......... ........... G · 50 > 50 CS5 AB 15 7.8 1.6 50 : ~ > 30 CS6 AB15 3.9 0.8 100 > 50 CS7 AB 16 12.4 1.5 - 8 CS8 AB16 16.7 ... 2.1. : > 50 CS9 AB16 7.4 _: 0.9 50 > 20 CS10 AB16 ............................. 12.4 .................. ... _: ......... ...... 1.5; 50 > 50 CS11 AB 16 ..0-5. 50: > 30

Table 30: Measurement of the latency time by Th i (2 μΜ) of the compositions CS1 to

CS11 The solutions of pramiintide at pH 6.6 and of co-polyamino acid AB15 and AB16 have a longer latency time in the presence of sodium chloride or sodium chloride and zinc.

Solutio not Cm polyaminoaci de I Co-concentration ! polyaminoacid 'e Ratio co- polyamino / pramlint ide [NaCl 1 i [ZnCb] Temp s of latenc e (h): mg / m The mM mol / mol (MM) (MM) CS7 AB16 12.4 1.5 10.5 <10 CS12 AB16 12.4 1.6 10.5 25 > 30 i CS14 AB16 10 · 1.3 8.4 50 > 30: CS 15 AB1.6 | 10 1.3 8.4 100 * 1 > 60 CS16 AB34 6.1 1.5 10 - - : <5. CS17 AB34 6.1 1.5 10 100 - > 40 CS19 AB33 i 5.7 1.5 10 - · <5 CS20 AB33 ; 5.7 1.5 10 50 > 10 CS21 AB33 5.7 1.5 i 10 50 T: •> 35

206

Solutio not Co- polyaminoaci of Copolyamino acid concentration Ratio co- polyamino / pramlint ide i [Naci ] [ZnCl ] Time to latenc e (H) mg / m L i mM mol / mol (MM) (MM) CS22 AB33 5.7 1.5 10 100 > 35 CS23 AB33 5.7 _: 1.5 10 100 1 > 40 CS24 AB35 6.3 1.6 10.4 " - <2 CS25 AB36 ............. 5.1 i 1.3 8 50 > 60 CS26 AB35 5.9 1.5 10 <10 CS27 AB35 3.6 r 0.91 6 25 > 43

Table 30a: Measurement of the latency time by ThT (2 μΜ) of the compositions CS7 and CS12, CS14 to CS17 and CS19 to CS27 [000960] The addition of salt alone or in the presence of zinc makes it possible on the one hand to achieve very satisfactory latency times and appreciably reduce the co-polyamino acid concentrations in the compositions.

Free D8: Stability of solutions of pramlintide 0.4 mg / ml and human insulin 100 ui / m! at pH 7.4 containing co-polyamino acid BB15.

Solution Concentration in  co-polyamino acid 1 BB15 Ratio i i BB15 / pramlintide i Latency (h) mg / mL _: mM <  mol / mol CN1 : ( * CN2 2.4 0.59 6 > 1.9 CN3 4 0.98 10 > 19

* Latency time not measured because turbid solution.

Table 31: Measurement of the latency time by ThT (1 μΜ) of the compositions CN1 to CN3.

The pramlintide and human insulin solution at pH 7.4 (CN1) devoid of co-polyamino acid is turbid.

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 / mi at pH 7.4 with latency times greater than 19 h for ratios BB15 / pramlintide molars greater than 6.

207

Example D9: 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 Bbls / pramlintide Co-concentration 1 polyaminoadde BB15 Latency (h) mol / mol mq / ml mM SHOUT - - * CU3 2 1.8 0.44 :> 0.5 CR2 3 2.7 0.66 > 2 CR3 4 3.6 0.88 > 6 CR4 5 _r AA 1.10 > 9 CU7 6 _μ .Μ 1/32 > 9 CU8 10 9 2.20 > 9

* Latency time not measured because turbid solution.

Table 32: Measurement of the latency time by ThT (2 μΜ) of the CRI solution at CR4 and CU3 at CU8.

[000963] A solution of pramlintide at 0.9 mg / ml and of human insulin 100 IU / ml at pH 7.4 (CRI) devoid of co-polyamino acid is turbid. The clear solutions of pramlintide at 0.9 mg / ml and 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 can be greater than 9 h for molar ratios BB15 / pramlintide greater than 5.

Example D10: 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.

Solution copolyamino Co-1 polyaminoadde concentration i _: Ratio i co- i polyamino acid / pramlintide Time I of; ? latency i (h) i 1 mg / mL m Μ 1 i mol / mol SHOUT ; - / CG2 BB15 5 10 1.22  2.45; 5.4 10.8 > 9 > 7 CG3 BB14 10 1.96 8.6 > 9 CG4 AB17 5 i 10 1.11 i 1.22; 4.9 9.8 > 2 > 5

208

Solution Co- polyamino Concentration in co- polyamino Ratio co- polyamino / pramlintide Latency (H) mg / mL m M mol / mol CG5 AB15 10 1.99 8.8 > 2 CG10 BB18 5 i io; 0.72 1.44 3.2 6.3 iY A d CG 11 BB9 5 10 I 1 i 2.01 4.4 8.8 > 4 '> 3 CG12 BB2 5 1 1.0 1.27 2.54 d 5.6 11.2 > 5 < > 6

* Latency time not measured because turbid solution.

Table 33: Measurement of the latency time by ThT (2 μΜ) of solutions CG2 to CG12.

The pramlintide and human insulin solution at pH 7.4 (CRI) is turbid.

The co-polyamino acids make it possible to obtain latency times greater than 1 hour under the conditions tested.

Example DU: Stability of solutions of pramlintide at 0.9 mg / ml and insulin lispro 100 IU / mi at pH 7.4 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 CD1 * CD3 2 ......... 13 ............. 0.44 0.8 CD4 3 . .. 2.7 0.66 > 2 CD 5 4 3.6 0.88 > 7 CD 6 ' 5 4.5 1.10 > 9 CD 7 6 5.4 1.22 > 9 1 CD8 10 9 1.32 > 9:

* Latency time not measured because turbid solution.

Table 34: Measurement of the latency time by ThT (2 μM) of the solutions CD1 and CD3 to CD8.

The pramlintide and lispro insulin solution at pH 7.4 (CD1) is turbid. The co-polyamino acids make it possible to obtain latency times greater than 0.8 hours under the conditions tested.

209

Example D12: 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 / I mg / mL mM CK1 - *: CK3 3 .2 0.45 > 0.5 CK4 4 2.7 0.61 > 5 CK5 6 4 0.90 > 5 CK 6 3 5.3 .1, 19. > 5 CK7 10 6.7 1.50 > 5 CK8 15 10 ^ Λ24 > 5

* Latency time not measured because turbid solution.

Table 35: Measurement of the latency time by ThT (2 μΜ) of solutions CK1 and CK3 to CK8.

The pramlintide and human insulin solution at pH 6.6 (CK1) is turbid. The clear solutions of pramlintide at 0.6 mg / mL and human insulin 100 IU / ml at pH 6.6 in the presence of co-polyamino acid BB15 have latency times greater than 0.5 h at molar ratio BB15 / pramlintide of 3, which can be greater than 5 h from a BB15 / pramlintide ratio of 4.

Example D13: 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.

Solution copolyamino Concentration  in co- • polyaminoadde Ratio co- polyamino / pramlintide Latency (h) .. mg / mL mM mol / I CM1 BB20 2.6 i 5.3 i 0.61 1.22 4 L 8 > 1 > 1 CM2 BB21 .. V 0.6 4 > 10 CM3 AB22 2.4 0.3 2 > 5 CM4 BB24 2.9 0.6 4 > 10 CM5 BB23 3 0.76 i 5 > 10 CM6 BB25 1.5 0.3 2 > 10 CM 7 8822 2.7 0.6 4 > 5 CM8 AB23 7.7 0.69 4.6 > 15 CM 9 B819 4.7 0.4 2.8 > 1: CM 10 AB28 2.3 0.3 : 2 > 10 CM 11 AB24 2.4 0.3 2 > 5 CM 12 AB25 2.6 0.3 2 > 5 CM 13 AB26 .... 0.3 2 > 1

210

Solution Co- polyamino Concentration in copolyamino acid Ratio co- polyamino / pramlintide Time i of: latency ·) (h) _: mg / mL mM mol / mol; 2.3 0.5 _: 3 > 10 CM 14 AB27 1.3 .......................... 2.7 0.15 0.3; 1: 2 i > 1 > 5 CM15 AB30 1.2 0.15 0.3 1 2 > 1 > 10 CM 16 A.B.31 1.3 2.5 0.15 0.3: 1 2 > 1  > 10 CM17 AB29 5.9 8.9 0.8 1J5 ... 5 7.6 > 1 > 5 CM 18 AB32 0.3 2 > 1

Table 36: Measurement of the latency time by ThhT (2 μΜ) of the solutions and CM1 to CM 18.

The pramiintide and human insulin solution at pH 6.6 (CK1) is turbid.

The co-polyamino acids make it possible to obtain latency times greater than 1 hour under the conditions tested.

Example D13A: Stability of solutions of pramiintide at 0.6 mg / ml and of human insulin 100 XU / ml at pH 6.6 in the presence of different co-polyamino acids and of different contents of sodium chloride and zinc chloride.

Solution Co- polyamino Co-polyamino acid concentration [NaCl] i [ZnCh] Time to <latency '(h) i mg / mL mM (MM) (MM) CQ1 AB14 6.3 1.87 100 1 > 5 i CQ2 AB15  7.8 1.6 " 0.23 > 2 CQ3 AB15 11.7 2.3 - 0.23 > 2 AB15 6.3 1.3 50 0.23 > 2 .......... CQ6 AB 15 ......... 7.3 L.6 ..... ..... 50 0.23 > 5 CQ7 AB15 3.9 0.8; 100 0.23 > 2 CQ8 AB15 ; 6.3 1.3 100 0.23 > 2 CQ9 AB 15 7.8 1.6 : too '0.23' 'L > 5 CQ10 AB16 7.4 ..... 0.9 .. 50 0.23 > 1 ^ .. CGII AB16 12.4 1.5 50 0.23 > 2 CQ12 AB16 . 7Λ 0.9 50 ; i > 2

Table 37: Measurement of the latency time by THh (2 μΜ) of solutions CQ1 to CQ12 [000968] The solutions of pramiintide and human insulin at pH 6.6 in the presence of the co-polyamino acids of AB14, AB15 and AB16, of chloride of sodium and zinc have latency times greater than 1 hour under the conditions tested. adding

211 sodium chloride or sodium chloride and zinc allows to increase the latency times.

Example D14: Stability of compositions having variable pramlintide concentrations and of human insulin at 100 IU / mL in the presence of co-polyamino acid AB24, m-cresol (29 mM), glycerin (174 mM) and zinc chloride (229 μΜ) at pH 6.6.

Solution Pramlintide concentration Concentration in copolyamino AB24 Ratio CO-: polyamino acid / pramlintide Latency (h) i (Mg / mL) mg / mL : mM mol / mol CF2 0.9 .... 5.4 0.67 3 :> 10 (12) CF3 ................. .............. 0.8 4.8 ........ ........ 0.6 3 > 10 (14.1) CF4 0.6 3 · δ 0.45 3 > 5 (5.51 CF5 0.3 ......... 1.8 ........ i 0.22 : 3 > 5 (5.6) CF6 0.2 1 0,125 225 ..........................> ..... 5 (5.4) ............ ............

Table 38: Measurement of the latency time by ThT (2 μΜ) of solutions CF2 to CF6.

The solutions of pramlintide of variable concentration and human insulin at 100 IU / mL at pH 6.6 are turbid (examples CF1A-E), The solutions of pramlintide of variable concentration and human insulin at 100 IU / mL at pH 6.6 in the presence of the co-polyamino acid AB24 have latency times greater than 5 h under the conditions tested.

D Π: Study of the stability of the compositions according to the invention

DU A: Preparation of the compositions

Composition DI: Preparation of a pramlintide solution at 0.9 mg / ml containing m-cresol (29 mM) and glycerin (174 mM) at pH 6.6.

By a process similar to that used in Example CH1 a solution of pramlintide at 0.9 mg / ml containing m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 is obtained . The solution is clear.

212

Composition D2: 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 method similar to that used in Example BHQ a solution of pramlintide at 0.9 rng / mL and co-polyamino acid BB15 at 10 mg / mL containing rnresol (29 mM) and ia glycerin (174 mM) at pH 6.6 is obtained. The solution is clear.

D IÏ B: 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>).

DUC: Dosage procedure for formulations:

The quantification of the purity of pramlintide and insulin and of the recovery of native peptide is carried out by reverse phase HPLC equipped with a CA18 column of size 4.6 x 150 mm with a particle size of 3.5. pm. Pramlintide is detected at a wavelength of 214 nm and insulin is detected at a wavelength of 2.76 nm. The elution is carried out in an aqueous mobile phase with a linear gradient of acetonitrile.

The recovery of pramlintide or insulin (%) at a time t represents the ratio between the area of the pramlintide peak or the area of the insulin 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 or isulin and the total area of all the peaks including pramlintide and its impurities.

213

D II D: Physical stability in cartridges at 37 ° C. of pramlintide solutions at 0.9 mg / ml in the presence of the co-polyamino acid BB15 _f of m-cresol (29 mM) and glycerin (174 mM) at pH 6, 6 or pH 7.4.

The DI, CY1, D2 and CY7 solutions are filtered (0.22 pm). 1 mL of solution is introduced into a 3 mL glass cartridge for an auto-injector pen. The cartridges are placed in an oven at 37 ° C in static. The cartridges are observed with a weekly frequency.

Solution BB15 copolyamino acid concentration pH Stability: physical: 37 ° C in cartridges (weeks) mg / mL DI - 6.6 <1 CY1 : . 7.4 · <1: D2 10 ..... 6.6 > 4 IT'S 7 .10 > 4

Table 39: Results of physical stability at 37 ° C. in cartridge of pramlinitide compositions at 0.9 mg / ml in the presence of co-polyamino acid BB15.

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.

Example DUC: Chemical stability in eartouches 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 D II D are analyzed by RP-HPLC chromatography.

Solution Co-polyamino acid BB15 concentration pH Pramlintide recovery (%) i 32 days - 37 ° C Purity pramlintide (%) mg / mL. T0 32 days 37 ° C DI - 6.6 <60 97.2 <50 CY1 7.4 <20 94.7 <50 D2 10 6.6 > 90 97.3 > 85 CY7 10 Z. 4 :> 60 i 98.6 > 60

Table 40: Results of the chemical stabilities of the pramlintide compositions at 0.9 mg / ml in the presence of co-polyamino acid BB15.

214 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 ° / o and can be greater than 85% at pH 6.6.

Example D EI: Physical stability in vial and cartridge at 30 ° C. of pramlintide sections at 0.9 mg / mL and 0.6 mg / mL in the presence of the co-polyamino acid BB15, of m-cresol (29 mM) and glycerin (174 mM) at pH 6.6.

The solutions Dl, CHI, D2 and CH8 are filtered (0.22 pm). 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 an oven at 30 ° C statically and are then observed every 2 weeks.

Solution BB15 copolyamino acid concentration Pramlintide concentration p H Physical stability 30 ° C in vial (week) Physical stability 30 ° C in <cartridge <i (week) mg / mL (Mg / ml.) Dl - 0.9 6.6 <7 <2 CH1 0.6 6.6 <7 D2 10 .0,9. 6.6 > 12 > 12 CH8 10 . . 03 > 12 > 12

Table 41: Results of physical stability in vial and in cartridge at 30 ° C. of the pramlintide compositions at 0.9 and 0.6 mg / ml in the presence of co-polyamino acid

BB.15.

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 / rnL pH 6.6 is less than 2 weeks. 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 physical stability at 30 ° C greater than 12 weeks in vial and in cartridge .

215

Example D II F: Chemical stability in vsai at 30 ° C. of solutions of pramlintide at 0.9 mg / ml and at 0.6 mg / ml in the presence of co-poiyamino acid BB15, of mcrésoi (29 mM) and of glycerin ( 174 mM) at pH 6.6.

The solutions described in the DUE example are analyzed by RP-HPLC chromatography.

Solution BB15 copolyamino acid concentration Pramlintide concentration Pramlintide recovery (%) Purity pramlintide (%) mg / mL (Mg / mL) 5 weeks 30 ° C T0 5 weeks 30 ° C DI ' - ...................................... 0.9 ......... ...................................... Γ <70 97.2  <60 D2 10 0.9 > 95 97.8 > 90 CH 8 10 0.6 > 95 94.6 > 90

Table 42: Results of chemical stability in via! at pramlintide compositions at 0.9 and 0.6 mg / mL at 30 ° C. in the presence of co-polyamino acid BB15 at pH 6.6.

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.

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 overlap greater than 95% and the purity of pramlintide is greater than 90% after 5 weeks at 30 ° C.

DMF example: Physical stability to vials and cartridges at 30 ° C of solutions of pramlintide at 0.6 mg / mL and insulin 100 IU / mL at pH 6.6 © r presence of co-polyamino acid BB15, of m-cresol (29 mM), glycerin (174 mM) and zinc at pH 6.6.

The CK8 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 an oven at 30 ° C statically and are then observed every 2 weeks.

216

Solution Concentration copolyamino acid BB15 Pramlintide concentration Insulin concentration i ·· Physical stability i 30 ° C in i vial (week) Physical stability 30 ° C in cartridge (week) mg / mL 1 ..... (mg / mL) ................ (IU / mL) CK1 0.6 100 : * CK8 10 i 0.6 100 > 3 > 12

* turbid solution as soon as it is prepared.

Table 43: Results of physical stability in via! and in cartridges at 30 ° C. compositions of pramlintide at 0.6 mg / ml, insulin 100 IU / ml and in the presence of copolyamino acid BB15 at pH 6.6.

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 BB15 has physical stability at 30 ° C greater than 3 weeks in vial and more than 12 weeks in cartridge.

Example D Π G: Chemical stability in via! at 30 ° C a solution of pramlintide at 0.6 mg / mi and insulin 1QO IU / mL at pH 6.6 in the presence of copolyamino acid BB15, m-cresoï (29 mM), glycerin (174 mM ) and zinc. The solution described in Example D II F is analyzed by RP-HPLC chromatography.

Solution Pramlintide recovery: (%): Purity ; pramlintide (%) Insulin recovery (%) | ? ^{L The} purity ^Insulin! i (%) i 5 weeks 30 ° C i T0 5 weeks  30 ° C 5 weeks 30 ° C i T0 5 weeks 30 ° C: CK8 > 90 96.8 > 90 > 90 97.9 1 > 90

Table 44: Results of chemical stability in vial at 30 ° C. of a composition of pramlintide at 0.6 mg / ml, of insulin 100 IU in the presence of co-polyamino acid BB15 at pH 6.6.

The solution of pramlintide at 0.6 mg / mL and insulin at 100 IU / mL at pH 6.6 is turbid.

The pramlintide solution at 0.6 mg / mL and insulin at 100 IU / mL at pH 6.6 in the presence of co-polyamino acid BB15 has a pramlintide coverage greater than 90% and the purity of pramlintide is greater than 90% after 5 weeks at

217 ° C in vial · The insulin recovery is more than 90% and the purity of insulin is more than 90% after 5 weeks at 30 ° C in vial.

Example D II H: 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 2.4 mg / mL AB24 co-polyamino acid, m-cresol (29 mM), glycerin (174 mM) and zinc at pH 6.6.

The CM11 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 an oven at 30 ° C statically and are then observed every 2 weeks. Cartridges are also placed in a static oven at 37 ° C and are observed weekly.

Solu Lion Concentration copolyaminoacid e AB24 Concentra pramlintid e Concentration Insulin Physical stability 30 ° Cen vial (weeks) Physical stability 30 ° C in cartridge (weeks) Stability • physical 37 ° C 'cartridge (weeks ) i mg / mL (Mg / mL) • (IU / mL) _: CK1 -V 0.6 100 * * * CM1 1 2.4 0.6 100 > 9 > 12 > 9

♦ turbid solution as soon as it is prepared.

Table 45: Results of physical stability in vial at 30 ° C and in cartridge at 30 and 37 ° C of the compositions of pramlintide at 0.6 mg / mL, insulin 100 IU / mL and in the presence of co-polyamino acid AB24 at pH 6.6.

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 D Π I: 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 solution described in Example D II H is analyzed by RP-HPLC chromatography.

218

Solution CM11 Recovery I pramlintide; (%) Pramlintide pu ret (%) Insulin recovery (%) Purity Insulin 1 (%) 9 weeks 30 ° C T0 9 weeks 30 ° C 9 weeks 30 ° C T0 9 weeks 30 ° C Vial > 88 96.7 > 90 > 90 97.4 > 90 Cartridge > 88 96.9 > 85 > 90 97.7 > 90

Table 46: Results of the chemical stabilities in vial and cartridge at 30 ° C. of the compositions of pramlintide at 0.6 mg / ml, of insulin 100 IU in the presence of copolyamino acid AB24 at pH 6.6.

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 a pramlintide coverage greater than 88% and a purity greater than respectively 90 and 85% after 9 weeks of storage at 30 ° C in via! and in cartridge. Under these conditions the insulin recovery is greater than 90% and the purity of insulin greater than 90% in vial and in cartridge.

Example D II J: 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 co-polyamino acid 8815, of m-cresol (29 mM), of glycerin (174 mM) at pH 6.6.

The CH8 solution is filtered (0.22 μm). 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 BB15 copolyamino acid concentration Concentration pramlintide pH Stability > physical < i 4 ° C i cartridge i : (month): mg / mL (Mg / mL). CH8 / 10 0.6 > 6

Table 47: Results of physical stability in a cartridge at 4 ° C. with a pramlintide composition at 0.6 mg / ml and in the presence of co-polyamino acid BB15 at pH 6.6.

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 in cartridges greater than 6 months.

219

Example D II K: Physical stability in a cartridge at 4 ° C. of solutions of pramlintide at 0.6 mg / ml at pH 6.6 and pH 7.4 in the presence of DMPG at 4.5 mM.

The CZO and CZ1 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) Concentration pramlintide i (mg / mL) pH excipients Stability 'physical i at 4 ° C in cartridge (month) CZO 4.5 0.6 6.6 m-cresol 29 mM Glycerin 174 mM <1.5 CZ1 4.5 0.6 ; 7.4 phenol 30 mM > Glycylglycine 8mM pH 7.4 Glycerin 174 mM <1.5

Table 48: Results of the physical stability in cartridge at 4 ° C. of the pramlintide compositions at 0.6 mg / ml and in the presence of DMPG at pH 6.6 and 7.4.

The pramlintide solutions at 0.6 mg / mL at pH 6.6 and at pH 7.4 have physical stability at 4 ° C. and in cartridges of less than 1.5 months (turbid solutions).

Example DHL: Pump stability of solutions of pramlintide at 0.6 mg / ml and human insulin at 100 IU / ml at pH 6.6 in the presence of the co-polyamino acid AB24 at 3.6 mg / MI.

The CF4 solution composed of 0.6 mg / ml of pramlintide and 100 IU / ml of human insulin at pH 6.6 in the presence of the co-polyamino acid AB24 at 3.6 mg / ml is filtered (0, 22 pm) and introduced into a 3 mL tank. for Insulin pump (Minimed 530G system manufactured by Medtronic). The pump is equipped with an infusion set (Quick set Paradigm 9/110 manufactured by Medtronic).

The insulin pump is placed in an oven at 37 ° C on an orbital shaker set at a speed of 100 rpm. The pump is regulated with a basal flow of 0.8 IU / h. Bolus injections of 6 IU are given 3 times a day for a total of 8 days.

[0001003] Table 49 presents the results of MFI measurements (Micro-Flow Imaging) and the assays performed by RP-HPLC on fractions collected between the ^7th and 8th ^ems stability formatting day.

220

Solution Particles <subvisible i (Micro Flow Imaging, MFI) Pramlintid recovery (%) Pramlintide purity i (%) Recovery nt j Insulin 'human (%) Purity  Insulin . (%) 1 week 37 ° C 1 week 37 ° C T0 1 week i e 37 ° C 1 week 37 ° C T0; î 1 I week _{37 oc} CM 11 0artLCuies> 10 μ Μ <6000 particles per i container * · > 95 97: · ³ i > 95 > 95 97. 4 > 95 particuless ^ ZS. IJM <600 particles per container *

* Standard USP <788> on the number of sub-visible particles in products for parenteral injections.

Table 49: Results of the chemical stability in a pump at 37 ° C. of the compositions of pramlintide at 0.6 mg / ml, of insulin 100 IU / ml and in the presence of co-polyamino acid AB24 at pH 6.6.

After a week of pump stability at 37 ° C, the solution of pramlintide at 0.6 mg / mL and human insulin at 100 IU / mL at pH 6.6 in the presence of copolyamino acid AB24 is clear and present a number of subvisible particles in accordance with standard USP <788>. Under these conditions, the recovery and purities of pramlintide and insulin are greater than 95%.

Example D II M: Pump stability of solutions of pramlintide at 0 _f 6 mg / mL and insulin lispro at 100 IU / mL at pH S, 6 in the presence of the co-polyamino acid AB24 at 3.6 mg / mL.

The CA5 solution composed of 0.6 mg / ml of pramlintide and 100 IU / ml of Iispro insulin at pH 6.6 in the presence of the co-polyamino acid AB24 at 3.6 mg / ml is filtered (0, 22 pm) and subjected to a pump stability test by a protocol identical to that described in Example D II L.

221

Solution· particles ; subvisible < 1 (Micro Flow i Imaging, i MFI) i Pramlintid recovery (%) Purity pramiintide (%); Lispro recovery (%) Purity Insulin (%) · 1 week i • 37 ° C 1 week  37 ° C T0 1 week 37 ° C 1 week 37 ° C T0 1 week at 37 ° C CA5 <6000 particles per container * > 95 97, 2 > 95 > 95 99.3 > 95; saiioil˧> 25 uM <600 particles i by i containing * · '

* USP criterion <788> on the number of sub-visible particles in products for parenteral injections.

Table 50: Results of the chemical stability at a pump at 37 ° C. of the compositions of pramiintide at 0.6 mg / ml, of insulin lispro at 100 IU / ml and in the presence of copolyamino acid AB24 at pH 6.6.

After a week of pump stability at 37 ° C, the pramiintide solution at 0.6 mg / mL and insulin lispro at 100 IU / mL at pH 6.6 in the presence of co-polyamino acid AB24 is clear and has a number of subvisible particles in accordance with standard USP <788>. Under these conditions, the recovery and purities of pramiintide and insulin lispro are greater than 95%.

E. PHARMACODYNAMY AND PHARMACOKINETICS

El: Protocol for measuring the pharmacokinetics of pramiintide and insulin formulations, [0001007] Domestic pigs of approximately 50 kg, previously catheterized at the jugular level, are fasted 2.5 hours before the start of the 'experience. In the hour preceding the injection of the pramiintide and insulin formulations, 3 blood samples are taken in order to determine the basal level of pramiintide.

222 [0001008] The injection of the formulations at a dose of 1.125 pg / kg for pramlintide and 0.1875 IU / kg for insulin is carried out subcutaneously at the level of the animal's flank using '' an insulin pen (Novo, Sanofi or Lilly) fitted with a 31 G needle.

[0001009] Blood samples are then taken every 4 minutes for 20 minutes and then every 10 to 60 minutes up to 3 hours. After each sample, the catheter is rinsed with a dilute solution of heparin.

The blood thus collected is collected in a K2EDTA tube and is centrifuged to isolate the plasma. Pramlintide levels in plasma samples are measured by the ELISA sandwich immunoassay method for each animal. Pharmacokinetic curves expressed as a delta of the basa level! are then plotted.

The following pharmacokinetic parameters were then determined by non-compartmental analysis with the Phoenix WinNonlin software:

- tmax pramlintide corresponding to the time necessary to reach the maximum concentration of pramlintide in the plasma;

AUCpram o-3omin corresponding to the area under the pramlintide concentration curve as a function of time between 0 and 30 minutes post-administration;

AUCpram 6o-i8omir> corresponding to the area under the curve of pramlintide concentrations as a function of time between 60 and 180 minutes after administration;

Ciast corresponding to the last quantifiable pramlintide concentration in the plasma;

- tiast corresponding to the time at which Ciast is observed.

[0001013] The tmax is commonly used to evaluate the start of absorption. AUCpram o-30min is commonly used to assess early exposure to pramlintide in plasma. AUCpram eo-isomin is used to assess late exposure to pramlintide in plasma. Ciast and hast allow studying late concentration levels.

223

E2: Pharmacokinetic results of pramlintide of the pramlintide and insulin formulations of examples CA2 and CA3

Exemp! e Rh Insulin e co- polyamino Pramlintid have (mg / mL) i Number of i pigs i CA1 / CA2 (double injection) 100 : 1 i i 8 CA3 100 · BB15 0.6 10

The pharmacokinetic results of pramlintide obtained with the compositions described in examples CA1 / CA2 and CA3 are presented in Figure. 2. Analysis of these profiles indicates that the composition of Example CA3 comprising the copolyamino acid BB15, 100 IU / mL. of insulin and 0.6 mg / ml of pramlintide (curve drawn with the squares corresponding to example CA3) makes it possible to obtain an absorption of pramlintide slower than that of the composition of the example in double injection comprising only pramlintide and insulin (curve drawn with the triangles corresponding to the example double injection CA1 / CA2). The pharmacokinetics of pramlintide are shown in the following table:

Example tmax pramlintide (Min) AUCpram 0- 30min (Min * PMOI / L ) AUCpram 6Q- ISOrn-n he clast pramlintide (Min) tiasl pramlin- ï tide (min) i CA1 / CA2 20 ± 10 2076 ± 1596 3286 ± 1951 12 p.m. 5 153 ± 40: CA3 77 ± 44 1006 ± 885 5989 ± 3146 28 ± 24 168 ± 25

224

E3: Results of pharmacokinetics of pramiintide of pramiintide and insulin formulations of examples CA1 / CA2 and CA4.

Exempl e Rh Insulin e co- polyamino Pramlintid e (Pg / mL) Number of pigs CA1 / CA2 i 100 - 8 CA4 100 AB24 0.6 12

The pharmacokinetic results of pramiintide obtained with the compositions described in examples CA1 / CA2 and CA4 are presented in Figure 3. The analysis of these profiles indicates that the composition of example CA4 comprising the copolyamino acid AB24, 100 IU / mL of insulin and 0.6 pg / mL. of pramiintide (curve drawn with the squares corresponding to example CA4) makes it possible to obtain a slower absorption of pramiintide than that of the composition of the example in double injection comprising only pramiintide and insulin (curve drawn with the triangles corresponding to the CA1 / CA2 double injection example). The pharmacokinetics of pramiintide are given in the following table:

Example tmax prarnlinti from (Min) AUCprsm 0- 30rnïn '(mm * prnol / L ) AUCpram 60- 180mln; i (min * pmoi / L; Clast pramlintid e (Min) tlast pramlintid e; • (min) i CA1 / CA2 20 ± 10 _____ 2076 ± 1596 3286 ± 1951 12 ± 5 153 ± 40 CA4 68 ± 23 749 ± 316 8064 ± 2963 34 ± 22 175 ± 17 i

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 ^ —F GpCj ^ra Formula I in which GpR is a radical of formulas II, II 'or II: HH HH R fi π _{0! J} ^ RN- ^ n'or _{Formub ir;} - GpA is a radical of formulas III or ΠΓ:

ΠΙ or

ΠΓ; 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 226 o if p is equal to 1 then a is equal to 0 or to 1 and GpA is a radical of formula ΙΙΓ and, o if p is equal to 2 then a is equal to 1, and GpA is a radical of formula HT; c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2; · D is an integer equal to 0, 1 or 2; - r is an integer equal to 0, 1 or 2, and o if r is 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 N-terminal position of the copolyamino acid, thus forming an amide function resulting from the reaction of an amine function in the N-terminal position of the co-polyamino acid precursor and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1 or 2 then the hydrophobic radical of formula I is linked to the copolyamino acid: * via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amine function of the precursor of the hydrophobic radical and an acid function carried by the precursor of the co-polyamino acid or * via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and 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 a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions - CQNH2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more unsaturated rings or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms; more precisely, R is a radical chosen from the group consisting of: o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 12 carbon atoms, if GpR is a radical of formula ΙΓ of 1 to 11 carbon atoms or if GpR. is a radical of formula II of 0 to 10 carbon atoms; o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 11 carbon atoms, if GpR is a radical of formula ΙΓ of 1 to 11 carbon atoms or if GpR is a radical of formula II from 0 to 10 carbon atoms, said alkyl radical carrying one or more -CONHz 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 radical chosen from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical comprising from 1 to 8 carbon atoms and optionally substituted by a radical derived from a saturated, unsaturated or aromatic cycle; 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, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and: o if p is equal to 1, x is between 9 and 25 (9 <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. 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 228 GpR, GpA, GpC, r and a as defined in claim 1. 3. Composition according to claim 1, characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which a = 1 and p = 2, represented by the following formula VI: - (GpR VgpA-4 GpCy ^{r 2} Formula VI in which GpR, GpA, GpC, r and a as defined in ia claim 1. 4. Composition according to any one of the preceding claims, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-poiyamino acids of formula VH below:

formula VII in which, "D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit)," Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, ® Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, or a radical chosen from the group consisting of an H, a linear acyl group from C2 to CIO, a branched acyl group from C3 to CIO, a benzyl, a terminal "amino acid" unit and a pyrogiutamate, * R? is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI, or a radical -NR'R, R. ' and R identical or different 229 being chosen from the group consisting of H, linear or branched or cyclic C2 to C10 alkyl, benzyl and said R 'and R alkyls which can together form one or more saturated, unsaturated and / or aromatic and / or aromatic carbon rings include heteroatoms, selected from the group consisting of O, N and S, ® X represents an H or a cationic entity selected from the group comprising metal cations; ® n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of copolyamino acid and 5 <n + m <250. 5. Composition according to Claim 4, characterized in that the copolyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the copoiyamino acids of formulas VII, in which Ri = R'- _; and R2 = R'2, of the following formula Vila: O

Formula Vila in which, - m, η, X, D and Hy as defined in ia claim 4, R'i 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'j 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 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. 230 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:

θ Formula Vllb in which m, X, D _; Ri and R? as defined in claim 4 and at least Ri or Rz is a hydrophobic radical of formula I, V or VI. 7. Composition according to any one of the preceding claims, characterized in that the molar ratio of 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, amylin receptor agonist or amylin analog is amylin. 9. Composition according to any one of the preceding claims, 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 also comprises a mealtime insulin. 11. Composition according to any one of the preceding claims, characterized in that the co-polyamnnoacid / insulin molar ratio is greater than or equal to S 1 n 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 231 of a reference composition comprising amylin, an amylin receptor agonist or an amine analog, but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals.