FR3084585A1 - PH 7 INJECTION SOLUTION COMPRISING AT LEAST ONE BASAL INSULIN WHICH PI IS BETWEEN 5.8 AND 8.5 AND AN AMPHIPHILIC COMPOUND CARRYING HYDROPHOBIC RADICALS - Google Patents

Abstract

The invention relates to a composition which is physically stable in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least: - a basal insulin whose isoelectric point (pI) is between 5.8 and 8.5, and - an amphiphilic compound comprising a hydrophilic backbone HB, substituted by at least one hydrophobic radical -Hy of formula I, - and a cation salt at least divalent.

Description

PH 7 INJECTION SOLUTION COMPRISING AT LEAST ONE INSULIN

BASAL OF WHICH THE PI IS BETWEEN 5.8 AND 8.5 AND AN AMPHIPHILIC COMPOUND CARRYING HYDROPHOBIC RADICALS [0001] The invention relates to insulin injection therapy (s) for treating diabetes.

The invention relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least one basal insulin whose isoelectric point (pi) is between 5.8 and 8.5 and an amphiphilic compound comprising a hydrophilic backbone HB carrying hydrophobic radicals.

It more particularly relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least one basal insulin whose isoelectric point (pi) is between 5.8 and 8.5 in combination with either a mealtime insulin or a gastrointestinal hormone or a mealtime insulin and a gastrointestinal hormone, and an amphiphilic compound comprising a hydrophilic backbone HB carrying hydrophobic radicals.

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

[0005] When type II diabetes is diagnosed in a patient, a gradual treatment is implemented. The patient first takes oral anti-diabetics (OAD) such as Metformin. When ADOs alone are no longer sufficient to regulate the level of glucose in the blood, a change in treatment must be made and, depending on the specificities of the patients, different combinations of treatments can be put in place. The patient can for example have a treatment based on a basal insulin type insulin glargine or insulin detemir in addition to the OAD, then then depending on the evolution of the pathology a treatment based on basal insulin and insulin prandial.

[0006] Furthermore, today, to ensure the transition from treatments with OADs, when these are no longer able to control the level of glucose in the blood, towards a basal insulin / mealtime insulin treatment, the GLP-1 RA analog injection is recommended.

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

[0008] The gastrointestinal hormones (Gut hormones) are also called satiety hormones. They include in particular GLP-1 RA (Glucagon like peptide-receptor agonist) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon), peptide YY, amylin, cholecystokinin, polypeptide pancreatic (PP), ghreline and enterostatin which have peptide or protein structures. They also stimulate the secretion of insulin in response to glucose and fatty acids and are therefore potential candidates for the treatment of diabetes.

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

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

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

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

[00013] Basal insulins maintain the patient's glycemic homeostasis, outside of periods of food intake. They act mainly to block endogenous glucose production (hepatic glucose). The daily basal insulin dose generally corresponds to 40-50% of the total daily insulin requirements. Depending on the basal insulin used, this dose is given in 1 or 2 injections, regularly distributed throughout the day. The most commonly used basal insulins are Levemir® (insulin detemir from NOVO NORDISK) and Lantus® (insulin glargine from SANOFI).

The basal insulins currently marketed can be classified according to the technical solution which makes it possible to obtain the prolonged action and to date two approaches are used.

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

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

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

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

Also, the substitution of ΙΆ21 has been designed to make insulin glargine stable at acidic pH and thus be able to formulate it as a solution for injection at acidic pH. During subcutaneous injection, the passage of insulin glargine from an acidic pH (pH 4-4.5) to a physiological pH (neutral pH) causes its precipitation under the skin. The slow redissolution of insulin glargine micro-particles ensures a slow and prolonged action.

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

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

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

The present invention aims to provide new amphiphilic compounds comprising a hydrophilic HB backbone comprising one or more hydrophobic grafts, said grafts comprising one or more imidazole radicals. These compounds make it possible to have a “modular” association with insulin glargine and also to obtain compositions comprising insulin glargine which are stable.

By modular association is meant that the association of said HB amphiphilic compound with insulin glargine may be more or less strong depending on the environment of said amphiphilic compound.

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

a basal insulin whose isoelectric point (pi) is between 5.8 and 8.5, and an amphiphilic compound comprising a hydrophilic HB backbone, substituted by at least one hydrophobic radical -Hy of formula I, and a cation salt at less divalent.

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 basal insulin whose isoelectric point (pi) is between 5.8 and 8.5, and a prandial insulin, and an amphiphilic compound comprising a hydrophilic backbone HB, substituted by at least one hydrophobic radical -Hy of formula I, and an at least divalent cation salt.

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 basal insulin whose isoelectric point (pi) is between 5.8 and 8.5, and a gastrointestinal hormone, and an amphiphilic compound comprising a hydrophilic backbone HB, substituted by at least one hydrophobic radical -Hy of formula I, and an at least divalent cation salt.

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 basal insulin whose isoelectric point (pi) is between 5.8 and 8.5, and a prandial insulin and a gastrointestinal hormone, and an amphiphilic compound comprising a hydrophilic HB backbone, substituted by at least one hydrophobic radical -Hy of formula I, and an at least divalent cation salt.

In one embodiment, the invention relates to a stable composition as defined above, characterized in that the hydrophobic radical -Hy is chosen from the radicals of formula I:

* - (GpR) r- (GpI) i - [(GpR) _r - (GpI) i '] t-GpC Formula I in which,

Gpl is a divalent radical, said radical comprising at least one imidazole unit

Im of formula III:

Formula III

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

Formula II,

Formula ΙΓ, or

Formula Π

GpC is a radical of formula IV:

Formula IV;

the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic skeleton HB or the above radicals (I, II, ΙΓ, Π III and IV) between them by amide functions;

- α, β and γ are identical or different integers equal to 0 or to 1;

b is an integer equal to 0 or 1;

c is an integer equal to 0 or 1;

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

- e is an integer equal to 0 or 1;

i and i 'identical or different are integers less than or equal to 6 and i + i' is greater than or equal to 1 and less than or equal to 6, 1 <i + i '<6, r and r' are integers equal 0, 1, 2 or 3;

if r is equal to 0 then the hydrophobic radical of formula I is linked to the hydrophilic skeleton HB via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction d an amine function of the precursor of the hydrophilic skeleton HB and an acid function carried by the precursor of the hydrophobic radical, and if r is equal to 1, 2 or 3 then the hydrophobic radical -Hy of formula I is linked to the hydrophilic skeleton HB:

o via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl of the hydrophilic skeleton HB, 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 hydrophilic skeleton HB or o via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and an amine function of the HB hydrophilic skeleton precursor;

t is an integer equal to 0 or 1;

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

Cx is a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and ll <x <25;

Γ, I and Γ, identical or different, are divalent radicals, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms,

I is a trivalent radical, chosen from the group consisting of an linear or branched alkyl radical comprising from 1 to 12 carbon atoms,

Im is an imidazolyl radical,

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, when several hydrophobic radicals are carried by a hydrophilic backbone HB then they are identical or different [00030] embodiment, the invention relates to a stable composition as defined above, characterized in that the hydrophobic radical -Hy is chosen from the radicals of formula I in which the radical of formula III is chosen from the radicals of formulas

Ilia:

Formula Ilia [00031] In one embodiment, the composition according to the invention is characterized in that Hy comprises between 15 and 100 carbon atoms.

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

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

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 40 and 50 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 40 carbon atoms.

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

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 30 and 40 carbon atoms.

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 6.0 and 8.0.

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

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

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

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

In one embodiment, when r - 2 then the GpR group linked to the hydrophilic skeleton HB is chosen from the GpRs of formula II and the second GpR is chosen from the GpRs of formula Π.

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

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

In one embodiment, said at least one hydrophobic radical --Hy is chosen from the radicals of formula I in which, t = 0, r '= 0 and i' = 0 of formula la, as defined below below:

* - (GpR) r- (GpI) i-GpC Formula la in which GpR, Gpl, GpC, r and i have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 2, r '= 0 and i' = 0 of formula Ib, as defined below :

* -GpRi-GpR- (GpI) i- -GpC Formula Ib in which GpRi is a radical of formula II,

H H

N-R-N— Formula II in which GpR, Gpl, GpC, R and i have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 2, r '= 0 and i' = 0 of formula Ib, as defined below :

* -GpRi-GpR - (Gpl) i- -GpC Formula Ib in which GpRi is a radical of formula II.

OO * _1L _r JL * _f „i 'Formula II in which GpR, Gpl, GpC, Gpl, R and i have the definitions given above.

_In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 1, r '= 0 and i' = 0 of formula le, as defined below :

* -GpR- (GpI) i-GpC Formula le in which GpR is a radical of formula II

H H

N ”R ^- N Formula II in which GpR, Gpl, GpC, R and i have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 1, r '= 0 and i' = 0 of formula le, as defined below :

* -GpR- (GpI) i-GpC Formula le in which GpR is a radical of formula ΙΓ.

O

He ^H

R N Formula ΙΓ in which GpR, Gpl, GpC, R and i have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 1, r '= 0 and i' = 0 of formula le, as defined below :

* -GpR- (GpI) i-GpC Formula le in which GpR is a radical of formula Π,

O O

Formula II in which GpR, GpC, Gpl, R and i have the definitions given above.

In one embodiment, said at least one hydrophobic radical --Hy is chosen from the radicals of formula I in which i = 1, r '= 0 and i' = 0 of formula Id, as defined above below:

* - (GpR) _r -GpI -GpC Formula Id in which GpR, GpC, Gpl and r have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which i = 3, r '= 0 and i' = 0 of formula le, as defined below :

* (GpR) r- (GpI) 3-GpC Formula le in which GpR, Gpl, GpC and r have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 0, r '= 0 and i' = 0 of formula If, as defined below :

* - (GpI) i-GpC Formula If in which Gpl, GpC and i have the definitions given above.

According to a particular embodiment i = 1.

According to a particular embodiment i = 2.

According to a particular embodiment i = 3.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which GpC is a radical of formula IV in which e = 0 and GpC is a radical of formula IVa.

Formula IVa in which B, b and Cx have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I, la, ïb, le, Id, le or If in which GpC is a radical of formula IV in which e = 1 and GpC is a radical of formula IVb.

Formula IVb in which c, d, B, b and Cx have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which GpC is a radical of formula IV in which e = 1 b = 0 and GpC is a radical of formula IVc.

Radical formula IVc in which c, d and Cx have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which GpC is a formula IV in which e = 0 b = 0 and GpC is a radical of formula IVd.

of

Formula IVd in which Cx has the definition given above.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le.

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

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

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

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

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II in which R is a radical divalent alkyl comprising 2 carbon atoms.

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

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

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula ΙΓ in which R is a radical divalent alkyia comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula ΙΓ in which R is a radical divalent linear alkyia comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula ΙΓ in which R is a radical divalent alkyia comprising 2 carbon atoms.

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula Π in which R is a radical divalent alkyia comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula Π in which R is a radical divalent linear alkyia comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula Π in which R is a radical divalent alkyia comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula Π in which R is a radical divalent linear alkyia comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II in which R is a radical divalent alkyl comprising 2 carbon atoms.

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, ΙΓ or H, 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, la, Ib, Id or le in which GpR is a radical of formula II, ΙΓ or Π in which R is an ether radical represented by the formula [00089] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II, ΙΓ or Π, in which R is a polyether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, ΙΓ or Π, 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, la, Ib, le, Id or le 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:

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le 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 I, la, Ib, le or le, GpR is chosen from formulas II, ΙΓ and / or Π and i = 1.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le or le in which GpR is a radical of formula II and i = 1.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le or le in which GpR is a radical of formula II and i = 1.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le or le in which GpR is a radical of formula II, i = 1 and Gpl is a radical of formula Ilia.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib or le, GpR is chosen from formulas II, ΙΓ and / or Π and i = 2 [ 00096] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib or le in which GpR is a radical of formula II and i = 2.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib or le in which GpR is a radical of formula II and i = 2.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le, GpR is chosen from formulas II, ΙΓ and / or Π and i - [00099] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II and i = 3.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula Π and i = 3.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II, i = 3 and Gpl is a radical of formula Ilia.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from group consisting of the radicals of formulas IVe, IVf or IVg below represented:

Formula IVe T .................................. Formula IVf LP: Formula IVg

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical is of formula IVe.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting radicals of formulas IVe, IVf or IVg in which b is equal to 0, corresponding respectively to formulas IVh, IVi, and IVj below represented:

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical corresponds to formula IV or IVe in which b = 0, and corresponds to the formula IVh.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If 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

he radicals represented by the formulas below: * * ch ₃ * * * * ch ₃ CH, * * * * * * H ₃ (T

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting radicals in which -Cx is chosen from the group consisting of linear alkyl radicals.

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

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

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

" ' ^X ' CH ₃ x = ll  '- CH x = 13

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

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

2 / '2.2''·' ^CH 3 x = is [000113] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:

Ç ^H 3 x = 16

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 5 25 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 10 18 carbon atoms.

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

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 20 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting radicals in which Cx is chosen from the group consisting of alkyl radicals represented by

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical corresponds to formula IV or IVe in which b = 0, and corresponds to the formula 30 IVh.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which

Cx is chosen from the group consisting of linear alkyl radicals comprising between 9 and 15 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising between 9 and 15 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If 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 9 or 10 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If 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 11 and 15 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If 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 11 and 13 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which

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

ch ₃ x = 9 ^ ch ₃ x = 11 ·· ch ₃ x = 13

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If 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 14 or 15 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the radical

GpC 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 [000127] In one embodiment, the composition is characterized in that the precursor of hydrophilic backbone HB carrying at least one hydrophobic radical is a polymer whose repeating units are chosen from the group of lysine, glutamic acid, aspartic acid, and ethers, in particular ethylene glycol and propylene glyco !.

According to a particular embodiment, the polyethers have two ends.

According to a particular embodiment, the ends of the polyethers are two amines, two acids or an amine and an acid.

In one embodiment, the composition according to the invention is characterized in that the hydrophilic backbone HB is a co-polyamino acid chosen from the polyglutamates below designated by PLG.

In one embodiment, the composition according to the invention is characterized in that the hydrophilic skeleton HB is a PLG co-polyamino acid carrying hydrophobic radicals, said hydrophilic skeleton is chosen from the co-polyamino acids of formula XXX below:

Ri

Hy

Formula XXX in which,

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

- Ri is a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of an H, a linear C2 to Cio acyl group, a branched C3 to Cio acyl group, a benzyl, a unit " amino acid "terminal and a pyroglutamate,

Rz is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid" unit and a pyroglutamate,

said copolyamino acid comprises at least one hydrophobic radical -Hy as defined above,

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

- if n = 0 then m> 1

- if m = 0 then n> 1

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

the ratio M between the number of hydrophobic radicals and the number of repeating units being between 0 <M <0.5 [000132] In one embodiment, the composition is characterized in that the copolyamino acid carrying hydrophobic radicals is chosen from the copolyamino acids of formula XXX in which n = 0 of the following formula XXXe:

in which m, X, D, Ri and R2 have the definitions given above and at least Ri or R2 is a hydrophobic radical Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe in which Ri is a radical hydrophobic -Hy and R2 is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe in which R.2 is a hydrophobic radical -Hy, and Ri is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe in which Ri and R2 are identical or different hydrophobic -Hy radicals.

In one embodiment, the composition is characterized in that the copolyamino acid carrying hydrophobic radicals is chosen from the copolyamino acids of formula XXXe in which m = 0 of formula XXXf below:

in which η, X, D, Ri and R2 have the definitions given above.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXf in which Ri is a radical hydrophobic -Hy and R2 is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXf in which Rz is a radical hydrophobic -Hy, and Ri is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXf in which Ri and Rz do not are not hydrophobic radicals -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXf in which Ri and Rz are identical or different hydrophobic -Hy radicals.

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

Ra

Formula XXXa in which,

- D and X have the definitions given above,

Ra and R'a, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of an H, a linear acyl group at C? to Cio, a branched C ₃ to Cio acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate, at least one of Ra and R'a being a hydrophobic radical -Hy,

Hy has the meaning given above.

Q being a spacer linking at least two chains of glutamic or aspartic PLG units of formula Q [- *] k linear or branched at least divalent consisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of atoms of nitrogen and oxygen and / or bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or radicals bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions and optionally carrying at least one hydrophobic radical

-Hy.

n + m has the same definition as given above.

In one embodiment, the radical or spacer Q [- *] k is represented by a radical of formula QII:

Q [- *] k = ([Q '] q) [- *] k where 1 <q <5, k> 2

Formula QII

The radicals Q 'being identical or different and chosen from the group consisting of the radicals of formulas QUI to QVI' below, to form Q [- *] k:

by a radical of formula WHO:

* - F _a - [cH ₂ j— F _a .— * ^{ti |} Formula QUI in which 1 <t _q <8 by a radical of formula QIV:

F _b —CH ₂

U!

- Fb '

U ₂

QIV formula in which:

At least one of ui or u ₂ is different from 0.

If ui + 0 then u'i Φ 0 and if u ₂ * 0 then u'z * 0, u'i and u ' ₂ are identical or different and, <u <4, <u'i <4, <ui <4, <u ' ₂ <4, <u ₂ <4;

by a radical of formula QV:

CH ₂ - - F _c .--- * * ----- F,

CH in which:

Formula QV v, v 'and v identical or different are integers> 0, and v + v' + v <15, by a radical of formula QVI:

* * in which :

Formula QVI w'i is different from 0, <w2 <1, wi <6 and w'i <6 and / or W2 <6 and w'2 <6 • with Fx = F _a , Fb, Fc, Fd, Fa ', Fb', F _c ', Fc and Fd' identical or different representing functions -NH- or -CO- and F _y representing a trivalent nitrogen atom -N =, • two radicals Q 'being linked together by a covalent bond between a carbonyl function, Fx = -CO-, and an amine function Fx = -NH- or F _y = N =, thus forming an amide bond.

In one embodiment k is 2, 3, 4, 5 or 6.

According to an embodiment k - 2.

According to one embodiment q = 1.

According to an embodiment k - 2 and q = 1.

In one embodiment, said radical Q 'is chosen from the radicals of formula QVI, in which W2 = 0 of formula QVI' as defined below:

QVI 'formula in which:

w'i is different from 0, <w2 <1, wi <6 and w'i <6 and / or w'2 <6 with Fd, and Fd 'identical or different representing functions -NH- or CO- and F _y representing a trivalent nitrogen atom -N =, two radicals Q 'being linked together by a covalent bond between a carbonyl function, Fx = -CO-, and an amine function F _x = -NH- or F _y = - N =, thus forming an amide bond, with in each of the radicals represented above, Fx = F _a , Fb, Fc, Fd, Fa ', Fb', F _c -, Fc and Fd- identical or different representing functions -NH- or -CO- and F _y representing a trivalent nitrogen atom -N =, two radicals Q 'being linked together by a covalent bond between a carbonyl function, Fx = -CO-, and an amine function F _x = -NH- or F _y - -N =, thus forming an amide bond. When a function F _x = F _a , Fb, Fc, Fd, Fa-, Fb ·, Fc ·, Fc and Fd 'Is not used in a connection between two Q', this function is then free and salified [ 000148] In one embodiment, if F _a and F _a - are -NH-, then t> 2.

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

In one embodiment, if F _a and F _a · are -CO- and -NH-, then t> l.

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

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

In one embodiment, if Fc, Fc · and Fc are 2 -NH- and 1 -CO- then at least one of the indices of - (CH2) - carrying a nitrogen is different from 0.

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

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

[000156] In one embodiment, if Fd and Fd · are -NH-, wi and w'i> 2 and / or W2 and w'2> 2.

In one embodiment, if Fd and Fd 'are -CO-, wi and w'i> 1 and / or W2 and w'2> 1.

In one embodiment, if Fd and Fd · are -CO- and -NH-, wi and w'i> 1 and / or W2 and w'2> 1.

The at least two chains of glutamic or aspartic PLG units being linked to Q [- *] k by a function Fx or F _y by a covalent bond to form an amide bond with a function -NH- or -CO- of the PLG.

In one embodiment, 1 <q <5.

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

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

III

whose precursor is a diamine.

Formula QUI [000163] In one embodiment, the precursor of the radical of formula QUI is a diamine chosen from the group consisting of ethylenediamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5- diaminopentane.

In one embodiment, tq = 2 and the precursor of the radical of formula QUI is ethylenediamine.

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

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

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

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

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

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

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

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

In one embodiment, tq = 4 and the precursor of the radical of formula QUI is aminobutanoic acid [000174] In one embodiment, the precursor of the radical of formula QQIII is a diacid.

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

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

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

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

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

QIV, * - F — CH ₂ / cH ₂ ); - O— £ cH ₂ ) - 'Mlu-J \ V ₂

-F _b ^ · u ₅ ² Formula QIV whose precursor is a diamine.

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

In one embodiment, u = u'i = 2, ui = l, u2 = 0 and the precursor of the radical of formula QIV is diethylene glycol diamine.

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

In one embodiment, u = u'z = 3, u'i = 4, ui = uz = 1 and the precursor of the radical of formula QIV is 4,9-dioxa-1,12-dodecanediamine.

In one embodiment, u = u'2 = 3, u'i = ui = 2, u2 = 1 and the precursor of the radical of formula QIV is 4,7,10-trioxa-l, 13- tridecanediamine.

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

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

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

In one embodiment, v = 4, v '= v = 0 and the precursor of the radical of formula V is lysine.

In one embodiment, v = 3, v '= v = 0 and the precursor of the radical of formula V is ornithine.

In one embodiment, v = 2, v '= v = 0 and the precursor of the radical of formula V is 2,3-diaminopropionic acid.

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

^v QV formula, the precursor of which is chosen from the group consisting of triacids.

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

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

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

QV formula, the precursor of which is chosen from the group consisting of triamines.

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

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

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

IRT,

whose precursor is a triamine.

Formula QVI [000197] In one embodiment, wz = 0 and the precursor of the radical of formula QVI is a triamine chosen from the group consisting of spermidine, norspermidine, and diethylenetriamine and bis (hexamethylene) triamine.

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

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

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

One embodiment, wz = 0 and the precursor of the radical of formula QVI is bis (hexamethylene) triamine.

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

QVI formula whose precursor is a tetramine.

In one embodiment, wz = 1 and the precursor of the radical of formula QVI is a tetramine.

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

[000205] In one embodiment, wz = 1 and the precursor of the radical of formula QVI is spermine.

In one embodiment, wz = 1 and the precursor of the radical of formula QVI is triethylenetetramine.

In one embodiment the precursor of the radical or spacer Q [- *] κ has 4 reactive functions, chosen from the group of amine functions and carboxylic acid functions.

In one embodiment the precursor of the radical or spacer Q [- *] k has 4 reactive functions and the precursor of the radical or spacer Q [- *] k is 1,2,3,4-butanetetraic acid .

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

IRT '

Formula VI ', the precursor of which is a triamine.

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

In one embodiment, wz = 0 and the precursor of the radical of formula QVI 'is spermidine.

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

In one embodiment, wz = 0 and the precursor of the radical of formula QVI 'is diethylenetriamine.

In one embodiment, wz = 0 and the precursor of the radical of formula QVI 'is bis (hexamethylene) triamine.

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

QVR,

Formula QVI 'whose precursor is a tetramine.

In one embodiment, w'h = 1 and the precursor of the radical of formula QVI 'is a tetramine.

In one embodiment, wz = 1 and the precursor of the radical of formula QVI 'is a tetramine chosen from the group consisting of spermine and triethylenetetramine.

In one embodiment, wz = 1 and the precursor of the radical of formula QVI 'is spermine.

In one embodiment, w? = 1 and the precursor of the radical of formula QVI 'is triethylenetetramine.

[000220] In one embodiment, all the F _x are linked to the PLG or to other Fx OR Fy.

In one embodiment, one or more Fx are free, that is to say are not linked to the PLG, or to another Fx, or to an F _y .

In one embodiment, an F _x is free, that is to say is not linked to the PLG, or to another Fx, or to an F _y .

In one embodiment, the Fx (s) of -CO- type is free, it is in the form of the carboxylic acid salt.

In one embodiment, the Fx of the -CO- free type is carried by a radical Q ′ of Formula QV.

In one embodiment, the Fx (s) of type -NH- is free, it is in the form of amine or ammonium.

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

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

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

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

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

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R _a and R 'a, identical are a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R _a and R ' _a , different are hydrophobic radicals -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which Ra is a radical hydrophobic -Hy and R'a is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one of the following co-polyamino acids of formula XXXa ':

minus one hydrophobic radical -Hy is chosen

Formula XXXa '

In which :

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

Q and Hy have the meanings given above, ni + mi represents the number of glutamic units or aspartic units of the co-polyamino acid chains carrying a radical -Hy, n ₂ + m ₂ represents the number of glutamic units or units aspartics of the co-polyamino acid chains not carrying a radical -Hy, ni + n ₂ - n 'and mi + m ₂ = m' n '+ m' represents the degree of polymerization DP of the co-polyamino acid, ie say the average number of monomeric units per chain of copolyamino acid and 5 <n '+ m'<250.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra and R 'a, identical are a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra and R 'a, different are hydrophobic radicals -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.

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

Formula XXXb in which,

D and X have the definitions given above,

Rb and R'b, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid" unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy,

Q and Hy have the meanings given above.

n + m has the same definition as given above.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which Rb and R ' b, identical are a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which Rb and R ' b, different are hydrophobic radicals -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which Rb is a radical hydrophobic -Hy and R'b is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.

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

P. O

11—— _H y cr n d- ©

Formula XXXb 'in which:

D and X have the definitions given above,

Q and Hy have the meanings given above.

Rb and R'b, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid" unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy, ni + mi represents the number of glutamic units or aspartic units of the co-polyamino acid chains carrying a radical -Hy, nz + mz represents the number of glutamic units or aspartic units chains of the co-polyamino acid not carrying a radical -Hy, ni + nz = n 'and ml + m2 = m', n '+ m' represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per copolyamino acid chain and 5 <n '+ m' <250.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb and R 'b, identical are a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb and R 'b, different are hydrophobic radicals -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.

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

Formula VIII

Formula VIII 'In one embodiment, the composition is characterized in that the copolyamino acid carrying hydrophobic radicals is chosen from the copolyamino acids of formulas XXX, XXXe, XXXf, XXXa, XXXb, XXXa' or XXXb 'in which the group D is a group -CH2-CH2- (glutamic unit).

In one embodiment, the composition is characterized in that the copolyamino acid carrying hydrophobic radicals is chosen from the copolyamino acids of formulas XXX, XXXe, XXXf, XXXa, XXXb, XXXa ', XXXb' in which group D is a group -CH2- (aspartic unit).

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.

[000259] 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 hydrophilic skeleton HB is a polylysine carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polylysines of formula

XXXX following:

in which,

Ri is a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of a -H or a terminal "amino acid" unit,

Rz is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of -OH, an amine group or a terminal "amino acid" unit,

said polyysine comprises at least one hydrophobic radical -Hy as defined above,

- if n = 0 then m> 1

- if m = 0 then n> 1

- n + m represents the degree of polymerization DP of the polyysine, that is to say the average number of monomeric units per chain of polyysine and 5 <n + m <250 and

the ratio M between the number of hydrophobic radicals and the number of repeating units being between 0 <M <0.5 [000264] In one embodiment, the composition according to the invention is characterized in that the skeleton hydrophilic HB is a polyisine carrying at least one hydrophobic radical and said hydrophilic skeleton is chosen from the polylysines of formula

In which, Ri, Rz, Hy, m and n have the meanings given above.

According to a particular embodiment, m = 0 and Ri and / or Rz is a hydrophobic radical -Hy.

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 hydrophilic skeleton HB is a polyalkylene glycol carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polyalkylene glycols of formula XXXXXa below

H

^p Formula XXXXXa in which,

Ri is a hydrophobic radical chosen from hydrophobic Hy radicals, or a radical chosen from the group consisting of -H or -OH,

R2 is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of -OH or -H,

- and at least one of Ri or R2 is a hydrophobic radical -Hy

- pn 'is an integer between 1 and 5, 1 <pn' <5

- pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per chain of polyalkylene glycol and 5 <n + m <250.

In one embodiment, the composition according to the invention is characterized in that the hydrophilic skeleton HB is a polyalkylene glycol carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polyalkylene glycols of formula XXXXXb following r ₂ Formula XXXXXb

Ri is a hydrophobic radical chosen from the hydrophobic radicals Hy, or a radical -OH,

Rz is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical -H,

- and at least one of Ri or Rz is a hydrophobic radical -Hy,

- pn 'is an integer between 1 and 5, 1 <pn' <5,

- pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per chain of polyalkylene glycol and 5 <n + m <250.

In one embodiment, the composition according to the invention is characterized in that the hydrophilic skeleton HB is a polyalkylene glycol carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polyalkylene glycols of formula XXXXXc below

Ri is a hydrophobic radical chosen from the hydrophobic radicals Hy, or a radical -OH,

Rz is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical -OH,

- pn 'is an integer between 1 and 5, 1 <pn' <5

- pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per chain of polyalkylene glycol and 5 <n + m <250.

In one embodiment, the precursors of the polyalkylene glycols of formula XXXXXa, XXXXXb or XXXXXc are chosen from the polyalkylene glycols of formulas XXXXX'a, XXXXX'b or XXXXX'c shown below:

H ₂ N .ο.

nh ₂ pn

Formula XXXXX'a h ₂ n

O

ΌΗ pn

Form XXXXX'b

pn

Formula XXXXX'c

In which:

- pn 'is an integer between 1 and 5, 1 <pn' <5,

- pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per chain of polyalkylene glycol and 5 <n + m <250.

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

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

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

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

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

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

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

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

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

The at least divalent cation salt is a cation salt of mineral origin chosen from the group of at least divalent cations derived from metals such as zinc or from alkaline earth metals such as magnesium or calcium.

In one embodiment, the at least divalent cation salt is a zinc salt.

In one embodiment, the at least divalent cation salt is a calcium salt.

In one embodiment, the at least divalent cation salt is a magnesium salt.

The salts of at least divalent cations are provided in the composition in the form of salts chosen from chlorides, phosphates, sulfates or hydroxides. In one embodiment, the at least divalent cation salts are present at a concentration of between 0.2 and 10 mM.

In one embodiment, the at least divalent cation salts are present at a concentration of between 0.4 and 8 mM.

In one embodiment, the at least divalent cation salts are present at a concentration of between 0.6 and 3 mM.

In one embodiment, the at least divalent cation salts are present at a concentration of between 0.2 and 10 mM per 100 U / ml of insulin glargine.

In one embodiment, the at least divalent cation salts are present at a concentration of between 0.4 and 8 mM per 100 U / ml of insulin glargine.

In one embodiment, the at least divalent cation salts are present at a concentration of between 0.6 and 3 mM per 100 U / ml of insulin glargine.

In one embodiment, the zinc salts are present at a concentration of between 0.2 and 10 mM.

In one embodiment, the zinc salts are present at a concentration of between 0.4 and 8 mM.

In one embodiment, the zinc salts are present at a concentration of between 0.6 and 3 mM.

In one embodiment, the zinc salts are present at a concentration of between 0.2 and 10 mM per 100 U / ml of insulin glargine.

In one embodiment, the zinc salts are present at a concentration of between 0.4 and 8 mM per 100 U / ml of insulin glargine.

In one embodiment, the zinc salts are present at a concentration of between 0.6 and 3 mM per 100 U / ml of insulin glargine.

[000305] The invention also relates to said amphiphilic compounds comprising a hydrophilic backbone HB carrying hydrophobic radicals of formula I and the precursors of said hydrophobic radicals.

Amphiphilic compounds comprising a hydrophilic HB backbone carrying hydrophobic radicals of formula I are soluble in distilled water at a pH between 6 and 8, at a temperature of 25 ° C and at a concentration of less than 100 mg / mL [000307] In one embodiment, the invention also relates to the precursors 15 of said hydrophobic radicals of formula I.

The invention also relates to said amphiphilic compound comprising a hydrophilic skeleton HB hydrophobic radical carriers of formula I.

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

The invention further relates to amphiphilic compounds carrying hydrophobic radicals.

The term “soluble” is intended to make it possible to prepare a solution in distilled water at 25 ° C. at a concentration of less than 100 mg / ml which is clear and devoid of particles.

The term "solution" means a liquid composition devoid of visible particles, using the procedure in accordance with European pharmacopoeias 8.0, in point 2.9.20, and American.

The term “physically stable composition” is understood to mean compositions which, after a certain period of storage at a certain temperature, satisfy the criteria of visual inspection described in the European, American and international pharmacopoeia, that is to say compositions which are clear and which do not contain visible particles, but which are also colorless.

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

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

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

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

[000318] The co-polyamino acid is a statistical or block co-polyamino acid.

The co-polyamino acid is a statistical co-polyamino acid in the chain of amino acid units, such as glutamic and / or aspartic units or lysine and / or ornithine.

The term “hydrophilic skeleton” is understood to mean a compound whose precursor (before grafting of the hydrophobic radical -Hy) has a LogP of less than 2 at pH 7.0.

According to a particular embodiment, the logP of the hydrophilic skeleton precursor is less than 1 at pH 7.0.

According to a particular embodiment, the logP of the hydrophilic skeleton precursor is less than 0 at pH 7.0.

LogP or Log Kow or partition coefficient is a measure of distribution of a compound in a mixture of immiscible solvent n-octanol / water. LogP can be measured using the shake flask or shake fiask method, or when this is not possible using the HPLC method (OECD Guideline for the testing of chemicals, 117, 30.03.89, Partition coefficient (n-octanol / water: HPLC method and 107, 07.27.95, Partition coefficient (n-octanol / water): Shake Flask Method). Said LogP of a compound being defined by the following equation:

logP - log (Coct / Ceau) in which Coct is the concentration of said compound in n-octanol and Ceau is the concentration of said compound in water.

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

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

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

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

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 by N-carboxyanhydride poly-methyl glutamate (GluOMe-NCA), N20 carboxyanhydride poly-benzyl glutamate (GluOBzl-NCA) and N-carboxyanhydride poly t-butyl glutamate (GluOtBu-NCA).

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

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained from a polyamino acid obtained by polymerization of an N-carboxyanhydride derivative of glutamic acid or of a derivative Ncarboxyanhydride of aspartic acid using as an initiator an organometallic complex of a transition metal as described in the publication Deming,

T.J., Nature 1997, 390, 386-389.

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 N35 carboxyanhydride of aspartic acid using as initiator ammonia or a primary amine as described in patent FR 2,801,226 and the references cited by this patent. In the same way, the initiator can be a polyamine in order to obtain polyamino acid comprising several PLGs. Said polyamines can be chosen from diamines, triamines and tetramines. The amines of these polyamines can be primary amines.

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 Ncarboxyanhydride of aspartic acid using as initiator hexamethyldisilazane as described in the publication Lu H.; et al., J. Am. Chem. Soc. 2007, 129, 14114-14115 or a silylated amine as described in the publication Lu H.; et al., J. Am. Chem. Soc. 2008, 130, 12562-12563.

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 can consist of a hydrolysis in an acid medium or a hydrolysis in a basic medium or be carried out by hydrogenation.

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

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

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid 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.

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

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

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

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

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

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

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

In the course of synthesis of the Hy intermediate compounds and during grafting the 20 conventional protection and deprotection techniques are used:

The one or more free carboxylic acid function (s) of Hy can be in protected form before grafting onto the PLG via an acid protecting group, this protection is carried out for example by esterification with using methanol, ethanol, benzyl alcohol or t-Butanol. After the grafting, the functions are deprotected, i.e. a deprotection reaction is carried out so that the carboxylic function (s) is (are) free or in the form of a salt. alkaline cation chosen from the group consisting of Na ⁺ and K ⁺ .

One or more amine function (s) may (may) be in protected form before grafting onto the PLG via an amine protecting group, this protection is carried out for example by acid or basic hydrolysis under heat via the phenylmethoxycarbonyl group or the 1,1-dimethylethoxycarbonyl group. After grafting, the functions are deprotected, that is to say that a deprotection reaction is carried out so that the function (s) amine is (are) free (s).

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

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

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

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

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

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

Biosimilar insulin glargine is being marketed under the brand Abasaglar® or Basaglar® by ELI LILLY.

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

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

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

In one embodiment, the compositions according to the invention comprise 150 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 250 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.

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

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the amphiphilic compound carrying hydrophobic radicals, or amphiphilic compound carrying hydrophobic radicals / basal insulin, is between 0.2 and 8.

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the amphiphilic compound carrying hydrophobic radicals, or amphiphilic compound carrying hydrophobic radicals / basal insulin, is between 0.2 and 6.

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the amphiphilic compound carrying hydrophobic radicals, or amphiphilic compound carrying hydrophobic radicals / basal insulin, is between 0.2 and 5.

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the amphiphilic compound carrying hydrophobic radicals, or amphiphilic compound carrying hydrophobic radicals / basal insulin, is between 0.2 and 4.

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the amphiphilic compound carrying hydrophobic radicals, or amphiphilic compound carrying hydrophobic radicals / basal insulin, is between 0.2 and 3.

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the amphiphilic compound carrying hydrophobic radicals, or amphiphilic compound carrying hydrophobic radicals / basal insulin, is between 0.2 and 2.

In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the amphiphilic compound carrying hydrophobic radicals, or amphiphilic compound carrying hydrophobic radicals / basal insulin, is between 0.2 and 1.

In one embodiment, the concentration of amhiphilic compound carrying hydrophobic radicals is at most 60 mg / ml.

In one embodiment, the concentration of amhiphilic compound carrying hydrophobic radicals is at most 40 mg / ml.

In one embodiment, the concentration of amhiphilic compound carrying hydrophobic radicals is at most 20 mg / ml.

In one embodiment, the concentration of amhiphilic compound carrying hydrophobic radicals is at most 10 mg / ml.

In one embodiment, the concentration of amhiphilic compound carrying hydrophobic radicals is at most 5 mg / ml.

In one embodiment, the concentration of amhiphilic compound carrying hydrophobic radicals is at most 2.5 mg / ml.

[000380] In one embodiment, the compositions according to the invention comprise a mealtime insulin. Prandial insulins are soluble at pH 7.

By mealtime insulin is meant a so-called rapid or "regular" insulin.

The so-called rapid meal insulins are insulins which must meet the needs caused by the ingestion of proteins and carbohydrates during a meal, they must act in less than 30 minutes.

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

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

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

[000386] The so-called very fast prandial insulins are insulins which are obtained by recombination and whose primary structure has been modified to reduce their action time.

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

In one embodiment, the meal insulin is insulin lispro.

[000389] In one embodiment, the meal insulin is insulin glulisine.

In one embodiment, the meal insulin is insulin aspart.

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

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

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

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

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

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

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

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

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

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

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

The proportions between the basal insulin whose isoelectric point is between 5.8 and 8.5 and the mealtime insulin are for example in percentage of 25/75, 30/70, 40/60, 50/50 , 60/40, 63/37, 70/30, 75/25, 80/20, 83/17, 90/10 for formulations as described above comprising from 60 to 800 U / mL. However, any other proportion can be achieved.

[000403] In one embodiment, the compositions according to the invention comprise a gastrointestinal hormone.

By “gastrointestinal hormones” is meant the hormones chosen from the group consisting of GLP-1 RA (Glucagon like peptide-1 receptor agonist) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative proglucagon), peptide YY, amylin, cholecystokinin, pancreatic polypeptide (PP), ghreline and enterostatin, their analogs or derivatives and / or their pharmaceutically acceptable salts.

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

[000406] In one embodiment, the gastrointestinal hormone is pramlintide or Symlin® ® (ASTRA-ZENECA).

[000407] In one embodiment, the gastrointestinal hormone is exenatide or Byetta®, its analogs or derivatives and their pharmaceutically acceptable salts.

[000408] In one embodiment, the gastrointestinal hormone is liraglutide or Victoza®, its analogs or derivatives and their pharmaceutically acceptable salts.

[000409] In one embodiment, the gastrointestinal hormone is lixisenatide or Lyxumia®, its analogs or derivatives and their pharmaceutically acceptable salts. In one embodiment, the gastrointestinal hormone is albiglutide or Tanzeum®, its analogs or derivatives and their pharmaceutically acceptable salts.

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

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

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

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

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

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

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

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

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

In one embodiment, the concentration of albiglutide, its analogs or derivatives and their pharmaceutically acceptable salts is between 5 to 100 mg / ml.

In one embodiment, the concentration of dulaglutide, its analogs or derivatives and their pharmaceutically acceptable salts is between 0.1 to 10 mg / ml.

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

In one embodiment, the compositions according to the invention are produced by mixing commercial solutions of basal insulin whose isoelectric point is between 5.8 and 8.5 and commercial solutions of GLP-1 RA, analog or GLP-1 RA derivative in volume ratios in the range of 10/90 to 90/10. [000424] In one embodiment, the composition according to the invention comprises a daily dose of basal insulin and a daily dose of gastrointestinal hormone. In one embodiment, the compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, between 0.05 and 0.5 mg / mL exenatide.

In one embodiment, the compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / mL of liraglutide.

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

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

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

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.04 to 0.5 mg / mL of exenatide.

In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.

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

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

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

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.04 to 0.5 mg / mL of exenatide.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.01 to 1 mg / ml of lixisenatide.

In one embodiment, the compositions according to the invention comprise 400 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and, from 5 to 100 mg / mL of albiglutide .

In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.1 to 10 mg / ml of Dulaglutide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.04 to 0.5 mg / mL of exenatide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.01 to 1 mg / ml of lixisenatide.

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 5 to 100 mg / ml of albiglutide .

In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.1 to 10 mg / ml of Dulaglutide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.04 to 0.5 mg / mL of exenatide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.

In one embodiment, the compositions according to the invention comprise 225 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.01 to 1 mg / mL of lixisenatide.

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 5 to 100 mg / ml of albiglutide .

In one embodiment, the compositions according to the invention comprise 225 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.1 to 10 mg / ml of dulaglutide .

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.04 to 0.5 mg / mL of exenatide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.01 to 1 mg / ml of lixisenatide.

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 5 to 100 mg / ml of albiglutide .

In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.1 to 10 mg / ml of Dulaglutide.

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

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

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

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

In one embodiment, the compositions according to the invention comprise 100 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 0.1 to 10 mg / ml of Dulaglutide.

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

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

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

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

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

In one embodiment, the 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 and Tris (trishydroxymethylaminomethane).

In one embodiment, the buffer is sodium phosphate.

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

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, 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. [000482] The transdermal, oral, nasal, vaginal, ocular, oral, pulmonary administration routes are also envisaged.

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

5.8 and 8.5 and a mealtime insulin.

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

5.8 and 8.5 and a gastrointestinal hormone, as defined above.

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

5.8 and 8.5, a meal insulin and a gastrointestinal hormone, as defined above.

The invention also relates to single-dose formulations at pH between

6.6 and 7.8 including a basal insulin whose isoelectric point is between

5.8 and 8.5 and a mealtime insulin.

The invention also relates to single-dose formulations at pH between

6.6 and 7.8 including a basal insulin whose isoelectric point is between

5.8 and 8.5 and a gastrointestinal hormone, as defined above.

The invention also relates to single-dose formulations at pH between

6.6 and 7.8 including a basal insulin whose isoelectric point is between

5.8 and 8.5, a meal insulin and a gastrointestinal hormone, as defined above.

The invention also relates to single-dose formulations at pH between

6.6 and 7.6 comprising a basal insulin whose isoelectric point is between

5.8 and 8.5 and a mealtime insulin.

The invention also relates to single-dose formulations at pH between

6.6 and 7.6 comprising a basal insulin whose isoelectric point is between

5.8 and 8.5 and a gastrointestinal hormone, as defined above.

The invention also relates to single-dose formulations at pH between

6.6 and 7.6 comprising a basal insulin whose isoelectric point is between

5.8 and 8.5, a meal insulin and a gastrointestinal hormone, as defined above.

In one embodiment, the single-dose formulations further comprise an amhiphilic compound carrying hydrophobic radicals as defined above. In one embodiment, the formulations are in the form of an injectable solution.

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

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

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

In one embodiment, the meal insulin is insulin lispro. In one embodiment, the meal insulin is insulin glulisine. In one embodiment, the meal insulin is aspart insulin.

In one embodiment, GLP-1 RA, analog or derivative of GLP-1 RA is chosen from the group comprising exenatide (Byetta®), liraglutide (Victoza®), lixisenatide (Lyxumia®), albiglutide (Tanzeum ®), dulaglutide (Trulicity®) or one of their derivatives.

[000502] In one embodiment, the gastrointestinal hormone is exenatide.

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

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

In one embodiment, the gastrointestinal hormone is albiglutide.

[000506] In one embodiment, the gastrointestinal hormone is dulaglutide.

The solubilization at pH between 6.0 and 8.0 of basal insulins whose isoelectric point is between 5.8 and 8.5, by amphiphilic compounds comprising a hydrophilic backbone HB carrying at least one radical hydrophobic according to the invention, can be observed and controlled in a simple manner, with the naked eye, by virtue of a change in appearance of the solution.

The solubilization at pH between 6.6 and 7.8 of basal insulins whose isoelectric point is between 5.8 and 8.5, by amphiphilic compounds comprising a hydrophilic HB backbone carrying at least one radical hydrophobic according to the invention, can be observed and controlled in a simple manner, with the naked eye, by virtue of a change in appearance of the solution.

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

The Applicant has also been able to verify that a prandial insulin mixed with a pH of between 6.0 and 8.0 in the presence of an amphiphilic compound comprising a hydrophilic HB backbone carrying at least one hydrophobic radical according to the invention and a basal insulin whose isoelectric point is between 5.8 and 8.5, retains its rapid insulin action.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin, the isoelectric point of which is between 5.8 and 8.5, and d 'An amphiphilic compound comprising a hydrophilic backbone HB carrying at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin, the isoelectric point of which is between 5.8 and 8.5, a solution of prandial insulin, and of an amphiphilic compound comprising a hydrophilic backbone HB carrying at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin, the isoelectric point of which is between 5.8 and 8.5, a solution of GLP-1 RA, an analogue or derivative of GLP-1 RA, and of an amphiphilic compound comprising a hydrophilic HB backbone carrying at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form . If necessary, the pH of the preparation is adjusted to pH between 6 and 8.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin, the isoelectric point of which is between 5.8 and 8.5, a solution of prandial insulin, a solution of GLP-1 RA or an analog or derivative of GLP-1 RA and an amphiphilic compound comprising a hydrophilic HB backbone carrying at least one hydrophobic radical according to invention, in aqueous solution or in lyophilized form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.

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

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

The invention also relates to compositions which further comprise an anion, cation or zwitterion chosen from ionic species different from at least divalent cations, 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.

By zwitterion is meant a species carrying at least one positive charge and at least one negative charge on two nonadjacent atoms.

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

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

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

In one embodiment, the organic anions are chosen from the group consisting of acetate, citrate and succinate [000524] 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 monovalent mineral origin.

In one embodiment, the cations of mineral origin are chosen from the group consisting of cations from alkali metals, in particular Na ⁺ and K ⁺ , [000531] In one embodiment, the zwitterions are chosen among the 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 from the group consisting of glycine, alanine, valine, isoleucine and leucine.

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

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

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

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

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

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

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

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

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

In particular, the zwitterions include as many negative charges as there are positive charges and therefore an overall charge 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, sodium phosphate and sodium sulfate.

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

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

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 2 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 3 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 4 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 5 mM.

[000552] In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 35 mM.

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

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 25 mM.

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

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 15 mM.

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

In one embodiment, the total molar concentration of ionic species in the composition is between 2 and 35 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 2 and 25 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 2 and 20 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 4 and 35 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 4 and 25 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 4 and 20 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 4 and 10 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 5 and 35 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 5 and 25 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 5 and 20 mM.

In one embodiment, the total molar concentration of ionic species in the composition is between 5 and 10 mM.

[000570] In one embodiment, the molar concentration of chloride ions in the composition is greater than or equal to 2 mM.

In one embodiment, the molar concentration of chloride ions in the composition is greater than or equal to 3 mM.

In one embodiment, the molar concentration of chloride ions in the composition is greater than or equal to 4 mM.

In one embodiment, the molar concentration of chloride ions in the composition is greater than or equal to 5 mM.

In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 35 mM.

In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 30 mM.

In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 25 mM.

In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 20 mM.

In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 15 mM.

In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 10 mM.

[000581] In one embodiment, the molar concentration of chloride ions in the composition is between 2 and 35 mM.

In one embodiment, the molar concentration of chloride ions in the composition is between 2 and 25 mM.

In one embodiment, the molar concentration of chloride ions in the composition is between 2 and 20 mM.

In one embodiment, the molar concentration of chloride ions in the composition is between 4 and 35 mM.

In one embodiment, the molar concentration of chloride ions in the composition is between 4 and 25 mM.

[000586] In one embodiment, the molar concentration of chloride ions in the composition is between 4 and 20 mM.

In one embodiment, the molar concentration of chloride ions in the composition is between 4 and 10 mM.

In one embodiment, the molar concentration of chloride ions in the composition is between 5 and 35 mM.

In one embodiment, the total molar concentration of chloride ions in the composition is between 5 and 25 mM.

In one embodiment, the total molar concentration of chloride ions in the composition is between 5 and 20 mM.

In one embodiment, the total molar concentration of chloride ions in the composition is between 5 and 10 mM.

EXAMPLES

Part. Δ. -_S.y. nthesedes cpnHy hydrophobic intermediates to obtain radicau x.-Hy

HYDROPHOBIC INTERMEDIATE COMPOUNDS

Example Al: molecule Al

Molecule 1: Product obtained by the reaction between / V-Boc ethylenediamine and phthalic anhydride [000592] To a solution of / V-Boc ethylenediamine (BocEDA, 20.0 g, 124.83 mmol) in toluene (300 mL) at room temperature is added phthalic anhydride (20.34 g, 137.34 mmol) then the mixture is heated to reflux in a DeanStark device for 6 h. After cooling to room temperature and standing overnight, a precipitate forms. Hexane (50 mL) is added dropwise. After 1 h, the precipitate is filtered, washed with diethyl ether (4 x 30 mL) and then dried at 35 ° C under reduced pressure. A crystalline powder of molecule 1 is obtained.

Yield: 28.4 g (78%)

Ψ NMR (DMSO-d6, ppm): 1.26 (9H); 3.16 (2H); 3.61 (2H); 6.54 (0.15H); 6.93 (0.85H); 7.75-7.94 (4H).

Molecule 2: Product obtained by the reaction between molecule 1 and trifluoroacetic acid [000594] To a solution of molecule 1 (28.4 g, 97.8 mmol) in dichloromethane (DCM, 142 mL) at room temperature is added trifluoroacetic acid (TFA, 30.15 mL, 391.3 mmol) dropwise while maintaining the temperature of the reaction medium <25 ° C. After overnight at room temperature, hexane (142 mL) is added dropwise and then ethyl acetate (5 mL). The precipitate is filtered, washed with diethyl ether (3 x 20 mL) and then dried at 35 ° C under reduced pressure. A solid of molecule 2 is obtained.

Yield: 18.1 g (61%)

NMR (CD ₃ OD, ppm): 3.26 (2H); 4.00 (2H); 7.78-7.95 (4H).

Molecule 3: Product obtained by the reaction between proline and palmitoyl chloride [000595] To a solution of L-proline (25.13 g, 218.29 mmol) in a mixture of water (121.5 mL) and of 10 N NaOH (27.3 mL, 272.86 mmol) at 0 ° C. is added dropwise a solution of palmitoyl chloride (33 mL, 109.14 mmol) in methylTHF (138 mL) with vigorous stirring. maintaining the temperature of the reaction medium <5 ° C. The reaction medium is stirred between 4 ° C and 20 ° C for 1.5 h then 3 h at room temperature. After cooling to 0 ° C, the pH is adjusted to 1.5 with concentrated hydrochloric acid (18.2 mL). The mixture is warmed to 20 ° C and the phases are separated. The organic phase is washed with a 5% aqueous solution of KHSO4 (3 x 100 mL), water (100 mL) and then concentrated under reduced pressure. The residue is then recrystallized from heptane (200 mL). A solid of molecule 3 is obtained.

Yield: 36.6 g (95%)

^X NMR (CDCl3, ppm): 0.87 (3H); 1.15-1.41 (24H); 1.57-1.74 (2H); 1.86-2.13 (3H); 2.35 (2H); 2.41-2.53 (1H); 3.39-3.52 (1H); 3.52-3.65 (1H); 4.37-4.44 (0.05H); 4.54-4.64 (0.95H); 7.83 (1H).

Molecule 4: Product obtained by the reaction between Fmoc-His (CITrt) -OH and 2chlorotrityl chloride resin [000596] A solution of Fmoc-His (CITrt) -OH (7.35 g, 11.24 mmol) in DCM (150 mL) is added to 2-CI-trityl chloride resin (1.5 mmol / g, 15 g), previously washed with DCM (2 x 150 mL), then A /, A / -diisopropylethylamine (DIPEA, 9.8 mL, 56.19 mmol) is added. After stirring overnight at room temperature, methanol (12 mL) is added and the medium is stirred at room temperature for 15 min. The resin is filtered, washed successively with DCM (3 x 150 mL), W-methyl-2pyrrolidone (NMP, 2 x 150 mL), DCM (2 x 150 mL) and methanol (3 x 150 mL) .

Molecule 5: Product obtained by the reaction between molecule 4 and a 90:10 NMP / piperidine mixture [000597] Molecule 4, previously washed with NMP (150 mL), is treated with a 90:10 NMP / piperidine mixture ( 165 mL). After 45 min of stirring at room temperature, the resin is filtered, washed successively with NMP (3 x 150 mL), methanol (3 x 150 mL) and NMP (3 x 150 mL).

Molecule 6: Product obtained by the reaction between molecule 5 and molecule 3 [000598] To a solution of molecule 3 (11.91 g, 33.69 mmol) in NMP (165 mL) is added l- [ bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3oxide hexafluorophosphate (HATU, 12.17 g, 32.01 mmol). After 30 min of stirring at room temperature, this solution is poured onto molecule 5 and DIPEA (7.8 mL, 44.92 mmol) is added. After stirring overnight at room temperature, the resin is filtered, washed successively with NMP (3 x 150 mL), methanol (3 x 150 mL) and NMP (3 x 150 mL).

Molecule 7: Product obtained by the reaction between molecule 6 and a 1% TFA / DCM mixture [000599] Molecule 6, previously washed with dichloromethane (150 mL), is treated with a 1% TFA mixture in DCM (150 mL) ). After 5 min of stirring at room temperature, the resin is filtered and the solvents are evaporated under reduced pressure. The molecule 7 is obtained in the form of a yellow oil which is used directly in the next step.

Yield: 12.1 g (crude reaction)

LC / MS (ESI +): 767.2 (calculated ([M + H] ⁺ ): 767.4)

Molecule 8: Product obtained by the reaction between molecule 7 and molecule 2 [000600] To a solution of molecule 7 (11.24 mmol) in DCM (84 mL) at 0 ° C are successively added DIPEA (5 , 7 mL, 32.84 mmol), (3dimethylaminopropyl) - / V'-ethylcarbodiimide hydrochloride (EDC, 2.31 g, 12.04 mmol) and Λ / hydroxybenzotriazole (HOBt, 1.84 g, 12, 04 mmol). After 5 min, molecule 2 (4.0 g, 13.13 mmol) is added and then the reaction medium is stirred overnight at room temperature. Cold water (50 mL) is added and the phases are separated. The aqueous phase is extracted with DCM (2 x 50 mL). The combined organic phases are washed with a 5% aqueous solution of KHSO4 (50 ml), an aqueous solution saturated with NaHCOs (50 ml) and an aqueous solution saturated with NaCl (2 x 50 ml). The organic phase is dried over NazSCU, filtered and concentrated under reduced pressure. Molecule 8 is obtained in the form of a white solid after purification by chromatography on silica gel (eluent: DCM, methanol).

Yield: 8.5 g (80%)

NMR (CDCh, ppm): 0.87 (3H); 1.00-1.49 (26H); 1.84-2.23 (5H); 2.37 (1H); 2.76 (1H); 3.07 (1H); 3.24-3.90 (6H); 4.30 (1H); 4.58 (1H); 6.57 (1H); 6.83 (1H); 7.01-7.13 (4H); 7.18-7.46 (11H); 7.64 (2H); 7.81 (2H); 8.34 (1H).

LC / MS (ESI +): 939.3 (calculated ([M + H] ⁺ ): 939.5)

Molecule Al A solution of molecule 8 (8.5 g, 9.05 mmol) and hydrazine monohydrate (1.32 mL, 27.14 mmol) is stirred overnight at room temperature in methyl tert- butyl ether (MTBE, 85 mL). The precipitate is filtered and washed with MTBE (55 mL) then the filtrate is concentrated under reduced pressure. A white solid of molecule Al is obtained after purification by chromatography on silica gel (eluent: DCM, methanol).

Yield: 5.5 g (75%)

NMR (CDCh, ppm): 0.88 (3H); 1.01-1.39 (28H); 1.92-2.37 (6H); 2.68-2.91 (3H); 3.01-3.27 (2H); 3.27-3.44 (1H); 3.44-3.61 (1H); 3.73-3.88 (1H); 4.40 (1H); 4.60 (1H); 6.60 (1H); 6.85 (1H); 7.02-7.21 (5H); 7.29-7.44 (10H); 8.77 (1H).

LC / MS (ESI +): 809.3 (calculated ([M + H] ⁺ ): 809.5)

Example A2: molecule A2 [000602] Molecule 9: Product obtained by peptide synthesis in solid phase [000603] Molecule 9 ([His (Trt)] 3ProC16) is obtained by the conventional method of peptide synthesis in solid phase on resin 2- chlorotrityl, successively using the amino acids Fmoc-protected Fmoc-L-His (Trt) -OH and Fmoc-Pro-OH, then palmitic acid (5 equivalents) and diisopropylcarbodiimide (5 equivalents) / cyano (hydroxyimino) acetate ethyl (5 equivalents) as coupling agents. 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 methanol after each coupling and deprotection step. The cleavage of the product from the resin is carried out using a DCM / HFIP 80:20 mixture.

Molecule A2 [000604] By a process similar to that used for the preparation of molecule 8 and applied to molecule 9 and ethylene diamine (20 equivalents), a white solid of molecule A2 is obtained after precipitation and trituration in the diethyl ether, purification by preparative HPLC (column C18, water / acetonitrile gradient) and lyophilization.

Yield: 0.3 g

LC / MS (ESI +): 1533.8 (calculated ([M + H] ⁺ ): 1533.9)

Part B - Synthesis of cp-polyamino acids hydrroEho_bes

No. CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER AND HYDROPHOBIC RADICALS bl t-EDAHisProC16-22PLG NaO o ^R fJ _h r Λ-J? - - Il m HA ü “» H i = 0.042, DP (m) = 24 Ri = H or pyroglutamate B2 t-EDAHis ₃ ProC16-22PLG _: n.cK _{; /} o 1. Vf V, .f _r . HH i = 0.048, DP (m) = 21 Ri = H or pyroglutamate

Example B1: co-polyamino acid B1 - sodium poly-L-glutamate modified at one of its ends by the molecule Al and having a number-average molar mass (Mn) of 3845 g / mol

Co-polyamino acid Bl-1: poly-L-benzylglutamate modified at one of its ends by the molecule Al.

In a flask previously dried in an oven, γ-benzyl-L-glutamate N15 carboxyanhydride (39 g, 148.1 mmol) is dissolved in anhydrous DMF (80 mL). The mixture is cooled to 4 ° C., then a solution of molecule Al (5.45 g, 6.73 mmol) in DMF (10 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 environment reacts! is then cooled to room temperature and poured dropwise into diisopropyl ether (IPE, 1350 mL) with stirring. The white precipitate is recovered by filtration, washed with ΓΙΡΕ (2 x 100 mL) and then dried under reduced pressure at 30 ° C to give a poly-L-benzylglutamate modified at one of its ends by the molecule Al.

Co-polyamino acid B1 [000606] Pd / AkOa (7.2 g) is added to a solution of co-polyamino acid Bl-1 (36 g) in N, Ndimethylacetamide (DMAc, 360 ml). The mixture is placed under hydrogen pressure (10 bar) and stirred at 60 ° C for 24 h. After cooling to room temperature and filtration of the catalyst on sintered glass and then on a 0.2 µm hydrophilic PTFE Omnipore membrane, a solution of water at pH 2 (2160 mL) is poured dropwise onto the DMAc solution over a period 45 min and with stirring. After 18 h with stirring, the white precipitate is recovered by filtration, washed with water (4 x 180 ml) and then dried under reduced pressure at 30 ° C. The solid (21.2 g) is suspended in TFA (130 mL) and the mixture is stirred for 24 h at room temperature then poured dropwise onto a 1: 1 (v / v) mixture of IPE / water. with stirring (280 mL). After 3 h of stirring, the precipitate is recovered by filtration, washed with ΙΊΡΕ (2 x 110 mL) and then dried under reduced pressure at 30 ° C. The solid obtained is dissolved in water (500 mL) 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 2 h . After neutralization at pH 7, the solution is filtered over 0.2 μm, diluted with ethanol 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 approximately 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: 26.0 mg / g

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

The calculated average molar mass of co-polyamino acid B1 is 4 119 g / mol aqueous HPLC-SEC (calibrating PEG): Μη = 3845 g / mol

Example B2: Co-polyamino acid B2 - sodium poly-L-glutamate modified at one of its ends by the molecule A2 and having a number-average molar mass (Mn) of 3236 g / mol

Co-oolyamino acid B2-1: poly-L-benzylglutamate modified at one of its ends by the molecule A2.

By a process similar to that used for the preparation of copolyamino acid Bl-1 applied to the molecule A2 (0.29 g, 0.19 mmol) and to y-benzyl-Lglutamate / V-carboxyanhydride (1.095 g, 4 , 16 mmol), the co-polyamino acid B2-1 is obtained.

Co-polyamino acid B2 [000608] Co-polyamino acid B2-1 (1.08 g) is diluted in TFA (3.8 mL), then the solution is cooled to 4 ° C. A 33% HBr solution in acetic acid (2.7 mL, 15 mmol) is then added dropwise. The mixture is stirred at room temperature for 3 h, then poured dropwise onto a 1: 1 (v / v) mixture of IPE and water with stirring (60 ml). After 2 h of stirring, the white precipitate is recovered by filtration, washed with ΙΊΡΕ (2x5 mL) then with water (2x5 mL). The solid obtained is then dissolved in water (20 mL) 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 30 min. After neutralization at pH 7, the theoretical concentration is adjusted to 20 g / L theoretical by adding water (10 mL). The solution is filtered on a 0.45 μm filter 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 pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 8.8 mg / g

DP (estimated by ¹ H NMR) = 21 therefore i = 0.048

The calculated average molar mass of the co-polyamino acid B2 is 3940 g / mol aqueous HPLC-SEC (calibrating PEG): Mn = 3236 g / mol

Part C - Compositions according to the invention

Example C1: Rapid insulin solution (Humalog®) at 100 U / mL [000609] This solution is a commercial insulin lispro solution marketed by the company ELI LILLY under the name of Humalog®. This product is a rapid analog insulin. The excipients in Humalog® are meta-cresol (3.15 mg / mL), glycerol (16 mg / mL), disodium phosphate (1.88 mg / mL), zinc oxide (to have 0 , 0197 mg of zinc ion / mL), sodium hydroxide and hydrochloric acid for adjusting the pH (pH 7-7.8) and water.

Example C2: Solution of rapid insulin lispro at 100-600 U / ml This solution is an insulin solution prepared from the powder of insulin lispro produced by the company Gan & Lee, which is a rapid insulin analog. The excipients used are meta-cresol, glycerol, zinc oxide, sodium hydroxide and hydrochloric acid for adjusting the pH (pH 7-7.8) and water. The zinc concentration is 300 μΜ per 100 IU / mL of insulin. The concentration of meta-cresol is 35 mM and that of glycerol is 184 mM.

Example C3: Basal analogous insulin solution (Lantus®) at 100 U / ml This solution is a commercial insulin glargine solution marketed by the company SANOFI under the name of Lantus®. This product is a basal analogue insulin. The excipients of Lantus® are zinc chloride (460 μΜ), meta-cresol (2.7 mg / mL), glycerol (85%) (20 mg / mL), Tween 20 (16 μΜ), l sodium hydroxide and hydrochloric acid for pH adjustment (pH 4) and water.

Example C4: Insulin glargine solution at 100-400 U / mL.

This solution is an insulin glargine solution prepared from insulin glargine powder produced by the company Gan & Lee. This product is a slow analog insulin. The excipients used are zinc chloride, meta-cresol, glycerol, sodium hydroxide and hydrochloric acid for adjusting the pH (pH 4) and water. The zinc concentration is 460 μΜ per 100 IU / mL of insulin. The concentration of the other excipients varies according to that of insulin glargine in order to obtain the desired concentrations in the final formulations.

Determination of the minimum ratios to dissolve insulin glargine

Protocol for determining the minimum concentration to dissolve insulin glargine at 50 U / mL at pH 7.1.

Concentrated solutions of zinc chloride, sodium chloride, m-cresol and glycerin are added to a stock solution of co-polyamino acid at pH 7.2 ± 0.3. 0.5 mL of an insulin glargine solution at a concentration of 100 U / mL, prepared according to example C3 or C4, is added to a volume of 0.5 mL of the copolyamino acid solution and of excipients for obtain a co-polyamino acid / insulin glargine composition 50 U / ml. The amount of excipients added is chosen so as to obtain a concentration of zinc chloride of 0-1 mM), of sodium chloride of 0-10 mM, of m-cresol of 35 mM and of glycerin of 184 mM in the composition copolyamino acid / insulin glargine 50 U / mL. The co-polyamino acid concentration varies from one preparation to another: solutions having copolyamino acid concentrations varying at most of 0.25 mg / ml are prepared in this way.

Following the addition of the glargine solution, a cloudiness appears. The pH is adjusted to pH 7.1 by adding concentrated NaOH and the solution is placed in an oven at 40 ° C for

1 night. After the night at 40 ° C the samples are visually inspected and subjected to a measurement of static light scattering at an angle of 173 ° using a zetasizer (Malvern). The minimum co-polyamino acid concentration to dissolve insulin glargine is defined as the lowest concentration for which the co-polyamino acid / insulin glargine mixture at pH 7.1 ± 0.1 is visually clear, 10 does not contain visible particles and has a scattered intensity of less than

2000 kcps / s.

Co-polyamino [Zn] (mM) [NaCl] (m M) [Copolyaminoaci de] (mg / mL) at the solubilization threshold for glargine 50 U / mL at pH 7 Ratio [Hy] / [insulin e glargine] (mol / mol) at the solubilization threshold B2 0.46 0 3.75 3.0 0.75 0 2.25 1.9 0.62 10 1.25 1.0 B1 0.23 0.23 0 10 4.0 2 3.0 1.6 0.84 0 2.5 2.0 0.76 10 1.5 1.1

Table 1: Minimum ratios for solubilizing insulin glargine.

The addition of ZnClz alone makes it possible to reduce the concentration of co-polyamino acid (mg / ml) at the threshold for solubilization of glargine. When NaCI is added in addition to ZnClz, this effect is improved.

Example CAI: Preparation of a concentrated copolyamino acid / insulin glargine composition at pH 7.2, according to a process using insulin glargine in liquid form (in solution) and a co-polyamino acid in liquid form (in solution).

To a stock solution of co-polyamino acid at pH 7.2 ± 0.3 is added a concentrated solution of zinc chloride To the mixture are added a concentrated solution of sodium chloride and a glargine solution at 100-400 IU / ml containing the excipients described in example C4. The concentration of excipients in the glargine solution is adjusted so as to obtain a zinc concentration (equal to Czmc = 1.89-2.38 mM mM), in meta-cresol of 35 mM and in glycerin of 184 mM in the co-polyamino acid / insulin glargine composition. The concentration of sodium chloride in the co-polyamino acid / insulin glargine composition is between 5 mM and 20 mM. Following the addition of the glargine solution, a cloudiness appears. The pH is adjusted to pH 7.2 ± 0.1 by addition of concentrated sodium hydroxide and the solution is placed in an oven at 40 ° C for 2 h until complete dissolution and obtaining a visually clear solution. Finally, a volume of concentrated Tween 20 solution is added to obtain a final concentration of 52 μΜ.

According to the CAI preparation process, polyamino acid / insulin glargine co20 compositions were prepared for example with an insulin glargine concentrations of 200 U / ml.

Example CA2: Preparation of co-polyamino acid / insulin glargine 200 U / ml compositions at pH 7.2 ± 0.1.

Co-polyamino acid / insulin glargine 200 U / ml compositions are prepared according to the method described in CAI so as to obtain a concentration of insulin glargine Cmsuime glargine = 200 U / ml and a concentration of co-polyamino acid Cco-polyaminoaclde ( mg / mL).

These compositions are presented in Table 2 ..

Com p ositio n Co-polyamino [Copolyaminoa eide] (mg / mL) [ZnCI ₂ ] (mM) [NaCl] (MM) Insulin e glargin e (U / mL) Aspect visual of the solution CA2-1 B1 8 1.89 10 200 limpid CA2-2 B1 8 2.38 5 200 limpid CA2-3 B1 8 2.38 10 200 limpid CA2-4 B1 8 2.38 20 200 limpid CA2-5 B2 7 1.89 10 200 limpid

Table 2: Insulin glargine compositions (200 U / mL) in the presence of different copolyamino acids.

Preparation process CB1: Preparation of a copolyamino acid insulin glargine / insulin lispro composition at pH 7.2 [000619] To a volume of the concentrated co-polyamino acid / insulin glargine composition at pH 7.2 described in example CAI is added a volume of a lispro solution described in example Cl or C2, to obtain the concentrations of insulin glargine and lispro desired in the co-polyamino acid / insulin glargine / insulin lispro composition. A volume of Tween 20 solution is also added to obtain a final concentration of 52 μΜ. If necessary, the pH is adjusted to pH 7.2 ± 0.1 by adding concentrated solutions of sodium hydroxide and hydrochloric acid. The resulting solution is visually clear. The concentration of zinc in the copolyamino acid / insulin glargine / insulin lispro composition is 1.12-2.58 mM), in sodium chloride is 5-20 mM, in meta-cresol is 35 mM and that of glycerin 230 mM .

Example CB1: Preparation of co-poiyamino acid compositions Bl / insulin glargine 200 U / mL / insulin lispro 66 U / mL at pH 7.2 [000620] Co-polyamino acid / insulin glargine 200 U / mL / insulin lispro 66 U / compositions mL are prepared according to the process described in CB1 so as to obtain a concentration of insulin glargine Cmsuiine glargine = 200 U / mL, a concentration of insulin lispro Cinsuime iispro = 66 U / mL and a concentration of co-polyamino acid Cœpolyamlnoaclde (iig / niL ).

These compositions are presented in Table 3 ..

Composition conception in copolya minoa eide Bl (mg / ML) [ZnCl · ] (MM) [NaCl] (MM) Insulin glargine (U / mL) Insulin lispro (U / mL) Aspect visual of the solution CB1-1 8 2.09 10 200 66 limpid CB1-2 8 2.58 10 200 66 limpid CB1-3 8 3.06 10 200 66 limpid CB1-4 8 2.58 5 200 66 limpid CB1-5 8 258 20 200 66 limpid

Table 3: Compositions of insulin glargine (200 U / mL) and insulin lispro (66 U / mL) in the presence of co-polyamino acid Bl.

gartie D .......-...... Results

Demonstration of the physical stability of the compositions according to the invention

DI free: Accelerated stability at 25 ° C in dynamics.

3 vials of 3 mL filled with 1 mL of co-polyamino acid / insulin glargine or co-polyamino acid / insulin glargine / mealtime insulin composition are placed vertically on an orbital shaker. The agitator is placed in an oven at 25 ° C. and the vials are subjected to stirring at 250 rpm. The vials are visually inspected daily / weekly to detect the appearance of visible particles or turbidity. This inspection is carried out according to the recommendations of the European Pharmacopoeia (EP 2.9.20): the vials are subjected to lighting of at least 2000 Lux and are observed in front of a white background and a black background. The number of days of stability corresponds to the time from which at least 2 vials have visible particles or are turbid.

The results of accelerated stability (obtained with different compositions) are presented in the following table:

Composition co-concentration polyamino acid Bl (Mg / ml) Stability in days CB1-1 8 > 50 CB1-2 ........ 8 .. > 50 CB1-3 8 > 50 CB1-4 8 > 50

Table 4: Results of accelerated stability in dynamics at 25 ° C. of the compositions

CB1-1 to CB1-4.

The compositions described allow good dynamic stability to be obtained.

Example D2: Accelerated stability at 30 ° C in static mode [000625] 5 vials of 3 mL filled with 1 mL of composition are placed vertically in an oven maintained at 30 ° C. The vials are visually inspected daily to detect the appearance of visible particles or turbidity. This inspection is carried out 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 of stability corresponds to the time from which at least half of the vials have visible particles or are turbid.

These results are in agreement with the US Pharmacopoeia (USP <790>).

The results of accelerated stability (obtained with different compositions) are presented in the table below.

Composition copolyamino acid Bl concentration (mg / mL) Stability in weeks CB1-1 8 > 16 CB1-2 8 > 16 CB1-3 8 > 16 CB1-4 8 > 16 CB1-5 8 > 16

Table 5: Results of accelerated stability in dynamics at 30 ° C. of the compositions

CB1-1 to CB1-5.

The compositions described allow good static stability to be obtained at 30 ° C.

Claims (14)

claims 1. Physically stable 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 basal insulin whose isoelectric point (pi) is between 5.8 and 8.5, and an amphiphilic compound comprising a hydrophilic HB backbone, substituted by at least one hydrophobic radical -Hy of formula I, and a cation salt at less divalent. 2. Composition in the form of an aqueous solution for injection, according to the preceding claim, characterized in that it also comprises a prandial insulin. 3. Composition in the form of an aqueous solution for injection, according to any one of the preceding claims, characterized in that it also comprises a gastrointestinal hormone. 4. Composition in the form of an aqueous solution for injection, according to any one of the preceding claims, characterized in that it further comprises an anion, cation or zwitterion chosen from ionic species different from at least divalent cations. 5. Composition in the form of an aqueous solution for injection, according to any one of the preceding claims, characterized in that the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine or an insulin biosimilar glargine. 6. Composition in the form of an aqueous solution for injection, according to any one of the preceding claims, characterized in that the mealtime insulin is human insulin or a recombinant human insulin. 7. Composition in the form of an aqueous solution for injection, according to any one of the preceding claims, characterized in that the prandial insulin is chosen from the group comprising insulin lispro (Humalog®), insulin glulisine (Apidra® ) and insulin aspart (NovoLog®). 8. Composition in the form of an aqueous solution for injection, according to any one of the preceding claims, characterized in that the gastrointestinal hormone is chosen from analogs or derivatives of GLP-1 RA chosen from the group consisting of exenatide or Byetta® (ASTRA-ZENECA), liraglutide or Victoza® (NOVO NORDISK), lixisenatide or Lyxumia® (SANOFI), albiglutide or Tanzeum® (GSK) or dulaglutide or Trulicity® (ELI LILLY & CO) , their analogs or derivatives and their pharmaceutically acceptable salts 9. Composition in the form of an aqueous solution for injection, according to any one of the preceding claims, characterized in that the hydrophobic radical -Hy is chosen from the radicals of formula I: * - (GPR) r (GPI) i - [(GPR) r - (GPI) r] Does GpC Formula I in which, Gpl is a divalent radical, said radical comprising at least one imidazole unit Im of formula III:

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

Formula II, O Il ^H * ™ -U — RN ~ * oo Formula ΙΓ, or • JLrJL. Formula II GpC is a radical of formula IV: Formula IV; the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic skeleton HB or the above radicals (I, II, ΙΓ, Π III and IV) between them by amide functions; - α, β and γ are identical or different integers equal to 0 or to 1; b is an integer equal to 0 or 1; c is an integer equal to 0 or 1; d is an integer equal! 0, 1 or 2; and if c is equal to 0 then d is equal to 1 or 2; e is an integer equal to 0 or 1; i and i 'identical or different are integers less than or equal to 6 and i + i' is greater than or equal to 1 and less than or equal to 6, 1 <i + i '<6, r and r' are integers equal 0, 1, 2 or 3; if r is equal to 0 then the hydrophobic radical of formula I is linked to the hydrophilic skeleton HB via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction d an amine function of the precursor of the hydrophilic skeleton HB and an acid function carried by the precursor of the hydrophobic radical, and if r is equal to 1, 2 or 3 then the hydrophobic radical -Hy of formula I is linked to the hydrophilic skeleton HB: o via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl of the hydrophilic skeleton HB, 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 hydrophilic skeleton HB or o via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and an amine function of the HB hydrophilic skeleton precursor; t is an integer equal to 0 or 1; B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms; Cx is a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and ll <x <25; Γ, I and Γ, identical or different, are divalent radicals, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms, I is a trivalent radical, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms Im is an imidazolyl radical, 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, when several hydrophobic radicals are carried by a hydrophilic backbone HB then they are identical or different 10. A stable composition according to claim 9, characterized in that the hydrophobic radical -Hy is chosen from the radicals of formula I in which the radical of formula III is chosen from the radicals of formulas Ilia:

Ilia formula 11. Composition according to any one of the preceding claims, characterized in that the precursor of the hydrophilic skeleton HB carrying at least one hydrophobic radical is a polymer whose repeating units are chosen from the group of lysine, the acid glutamic, aspartic acid, and ethers, including ethylene glycol and propylene glycol. 12. Composition according to any one of the preceding claims, characterized in that the hydrophilic skeleton HB is a co-polyamino acid carrying carboxylate charges and hydrophobic radicals, said hydrophilic skeleton is chosen from the co-polyamino acids of formula XXX below:

in which, Formula XXX - D independently represents either a -CHz- group (aspartic unit) or a -CH2-CH2- group (glutamic unit), - Ri is a hydrophobic radical chosen from hydrophobic radicals Hy, or a radical chosen from the group consisting of an H, a linear acyl group from Cz to Cio, a branched acyl group from C3 to Cio, a benzyl, an "acid" unit "terminal" amine and a pyroglutamate, Rz is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid" unit and a pyroglutamate, said copolyamino acid comprises at least one hydrophobic radical -Hy as defined above, - X represents a cationic entity chosen from the group comprising alkaline cations; - if n = 0 then m> 1 - if m = 0 then n> 1 - n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of co-polyamino acid and 5 <n + m <250. 13. Composition according to any one of the preceding claims, characterized in that the hydrophilic skeleton HB is a polylysine carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polylysine of formula XXXX below:

in which, FORM XXXX Ri is a hydrophobic radical chosen from hydrophobic Hy radicals, or a radical chosen from the group consisting of an -H or a terminal "amino acid" unit, Rz is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of -OH, an amine group or a terminal "amino acid" unit, said polylysine comprises at least one hydrophobic radical -Hy as defined above, - if n = 0 then m> 1 - if m = 0 then n> 1 - n + m represents the degree of polymerization DP of the polylysine, that is to say the average number of monomeric units per polylysine chain and 5 <n + m <250. 14. Composition according to any one of the preceding claims, characterized in that the hydrophilic skeleton HB is a polyethylene glycol carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polyethylene glycol of formula XXXXX below

in which, Ri is a hydrophobic radical chosen from hydrophobic Hy radicals, or a radical chosen from the group consisting of -H or -OH, Rz is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of -OH or -H, - and at least one of Ri or Rz is a hydrophobic radical -Hy - pn 'is an integer between 1 and 5, 1 <pn' <5 - pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per chain of polyalkylene glycol and 5 <n + m <250.