EP3142686A2

EP3142686A2 - Rapid-acting insulin composition comprising a substituted anionic compound and a polyanionic compound

Info

Publication number: EP3142686A2
Application number: EP15726556.2A
Authority: EP
Inventors: Olivier Soula; Richard Charvet; Bertrand Alluis
Original assignee: Adocia SAS
Current assignee: Adocia SAS
Priority date: 2014-05-14
Filing date: 2015-05-15
Publication date: 2017-03-22
Also published as: WO2015173427A4; US20160082106A1; WO2015173427A2; WO2015173427A3; US9795678B2

Abstract

The invention relates to a composition, in the form of an aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound having a non-saccharide structure and at least one polyanionic compound different from the substituted anionic compound.

Description

The present invention relates to a fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound.

Since the production of insulin by genetic engineering, in the early 80s, diabetic patients benefit from human insulin to treat themselves. This product has greatly improved this therapy since the immunological risks associated with the use of non-human insulin, in particular pork, are eliminated. However, human insulin injected subcutaneously has a hypoglycemic effect only after 60 minutes, which implies that diabetic patients treated with human insulin should proceed with the injection 30 minutes before the meal.

[0003] One of the problems to be solved to improve the health and comfort of diabetic patients is to provide them with insulin formulations which make it possible to provide a hypoglycemic response that is faster than that of human insulin and, if possible, approaching the physiological response of the healthy person. The secretion of endogenous insulin in the healthy individual is immediately triggered by the increase in blood glucose. The goal is to minimize the time between insulin injection and the start of the meal.

[0004] Today, it is accepted that the provision of such formulations is useful so that the management of the disease is the best possible.

[0005] Genetic engineering has made it possible to provide an answer with the development of fast analogous insulins. These insulins are modified on one or two amino acids to be more quickly absorbed into the blood compartment after a subcutaneous injection. These insulins lispro (Humalog ^® , Lilly), aspart (Novolog ^® , Novo Nordisk) and glulisine (Apidra ^® , Sanofi Aventis) are stable solutions of insulin with a hypoglycemic response faster than that of human insulin. Therefore, patients treated with these fast analog insulins can proceed to insulin injection only 15 minutes before the meal.

The principle of fast analogous insulins is to form hexamers at a concentration of 100 IU / mL to ensure the stability of insulin in the commercial product while promoting the very rapid dissociation of these hexamers into monomers after injection sub- cutaneous to obtain rapid action.

Human insulin as formulated in its commercial form, does not allow to obtain a close hypoglycemic response in terms of kinetics of the physiological response generated by the start of a meal (increase in blood sugar), because at the concentration of use (100 IU / mL), in the presence of zinc and other excipients such as phenol or m-cresol, it assembles in hexamer form while it is active in the form of monomer and dimer. Human insulin is prepared in the form of hexamers to be stable for 2 years at 4 ° C because in the form of monomers, it has a very high propensity to aggregate and fibrillate which makes it lose its activity. Moreover, in this aggregated form, it presents an immunological risk for the patient.

The dissociation of hexamers into dimers and dimers into monomers delays its action by nearly 20 minutes compared to a fast analog insulin (Brange J, et al, Advanced Drug Delivery eview, 35, 1999, 307-335).

In addition, the kinetics of passage of insulin analogs in the blood, and their kinetics of glucose reduction, are not optimal and there is a real need for a formulation having an even shorter action time. to approach the kinetics of endogenous insulin secretion in healthy people.

The company Biodel has proposed a solution to this problem with a human insulin formulation comprising EDTA and citric acid as described in patent application US200839365. EDTA by its ability to complex zinc atoms and citric acid by its interactions with the cationic regions present on the surface of insulin is described as destabilizing the hexameric form of insulin and thus reducing its time. action.

However, such a formulation has the particular disadvantage of dissociating the hexameric form of insulin which is the only stable form capable of meeting the stability requirements of the pharmaceutical regulations.

Also known in the name of the applicant, PCT application WO2010 / 122385 and WO2013 / 064787 which describe human insulin formulations or the like and a polysaccharide or a substituted oligosaccharide comprising carboxyl groups.

However, the requirements resulting from the chronic and intensive use or even the pediatric use of such formulations lead those skilled in the art to seek to use excipients whose molecular weight and size are the smallest possible for facilitate its elimination.

The polysaccharides described in applications WO 2010 / 122385A1 and US 2012 / 094902A1 as excipients are compounds consisting of chains whose lengths are statistically variable and which have a great wealth of possible interaction sites with protein active ingredients. This richness could induce a lack of specificity in terms of interaction and a smaller and better defined molecule could allow to be more specific on this subject. In addition, a molecule with a well-defined skeleton is generally more easily traceable (MS / MS for example) in biological media during pharmacokinetic or ADME experiments (administration, distribution, metabolism, elimination) by compared to a polymer that generally gives a very diffuse and noisy signal in mass spectrometry.

In contrast, it is not excluded that a well-defined and shorter molecule may have a deficit of possible interaction sites with protein active ingredients. Indeed, because of their reduced size they do not have the same properties as polysaccharide polymers because there may be loss of the polymer effect.

The Applicant has, however, succeeded in developing formulations that can accelerate insulin using a substituted anionic compound in combination with a polyanionic compound.

In addition, as in the case of the use of polysaccharides, the hexameric nature of the insulin is not affected, so the stability of the formulations is not affected, as is confirmed by the examples of a combination state of human insulin or lispro analog insulin in circular dichroism in the presence of substituted anionic compounds according to the invention, and optionally of polyanionic compound.

The present invention solves the various problems described above, in whole or in part, since it can in particular to achieve an insulin formulation, human or the like, capable after administration, to accelerate the passage of human insulin or its analogues in the blood and reduce blood sugar more rapidly compared to the corresponding commercial insulin products.

The invention consists of a composition, in the form of an aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound of non-saccharide structure and at least one polyanionic compound different from said substituted anionic compound.

In one embodiment, the pH of the composition is between 6 and 8.

By "aqueous solution" is meant a solution within the meaning of the European Pharmacopoeia.

The solution according to the invention can thus meet the European Pharmacopoeia 8.0 which defines an injectable preparation of soluble insulin has the characteristics of colorless liquid, non-opalescent, free of foreign substances; of the traces of very fine sediments that can be deposited during storage (01/2008: 0834).

The solution according to the invention may be a non-opalescent liquid, or even clear.

According to the European Pharmacopoeia 8.0 in point 2.2.1. a liquid is considered limpid when it has an opalescence which is not more pronounced than that of the control suspension I, which has an opalescence value of 3 NTU. The opalescence of the solution can be determined by the visual method and / or by the instrumental method, called turbidimetry. These methods are defined in European Pharmacopoeia 8.0 under 2.2.1.

In particular, the solution according to the invention has a turbidity less than or equal to 3 NTU according to the different methods described in European Pharmacopoeia 8.0 in section 2.2.1.

By "non-saccharide structure" is meant that these compounds do not contain in their saccharide unit structure, whether in cyclic form or in open, reduced or oxidized form.

By "saccharide unit" is meant pentoses, hexoses, uronic acids, and N-acetylhexosamines in cyclic form or in open form, oxidized or reduced.

In one embodiment, the compositions according to the invention are sterilized by 0.22 μm membrane filtration, for example by filtration on a SLGV033RS membrane, Millex-GV from Millipore, 0.22 μm PVDF membrane.

In one embodiment, the pH of the composition is between 6 and 8.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound of non-saccharide structure comprises a hydrocarbon radical R at least monovalent comprising from 3 to 12 carbon atoms, optionally comprising at least one a function chosen from ether, alcohol and carboxylic acid functions,

said hydrocarbon radical R carrying at least one AA radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative comprising a phenyl group or an indole group, substituted or unsubstituted, said AA radical being attached to the hydrocarbon radical R:

either directly via a function F chosen from amide, carbamate or urea functions, resulting from a reaction between the amine of the amino acid aromatic and a function of the precursor of the hydrocarbon radical R chosen from carboxylic acid, amine and alcohol functions,

either via a spacer E which is an at least divalent radical, comprising from 2 to 6 carbon atoms, E being linked on the one hand to the hydrocarbon radical R by a function F 'chosen from amide, carbamate or urea functions, and linked on the other hand to the AA radical by a function F "chosen from amide, carbamate and urea functions, resulting from a reaction between the amine of the aromatic amino acid and a function of the spacer E selected from the functions carboxylic acid, amine and alcohol,

said substituted anionic compound comprising at least two carboxylic acid functions in the form of alkali metal salt salts selected from the group consisting of Na ⁺ and K

In one embodiment, E is an at least divalent radical, linear or branched alkyl.

In one embodiment, E represents a linear or branched, saturated or unsaturated hydrocarbon radical comprising from 2 to 6 carbon atoms, optionally comprising at least one functional group chosen from alcohol and carboxylic acid functional groups. In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound of non-saccharide structure comprises a hydrocarbon radical R at least monovalent comprising from 3 to 12 carbon atoms, optionally comprising at least one a function chosen from ether, alcohol and carboxylic acid functions,

or directly via a function F chosen from amide, carbamate or urea functions, resulting from a reaction between the amine of the aromatic amino acid and a function of the precursor of the hydrocarbon radical R chosen from carboxylic acid, amine and alcohol,

or via a spacer E which is a divalent radical comprising from 2 to 6 carbon atoms, E being linked on the one hand to the hydrocarbon radical R by a function F 'chosen from amide, carbamate or urea functions, and linked to other part of the AA radical by a function F "chosen from amide, carbamate and urea functions, resulting from a reaction between the amine of the aromatic amino acid and a function of the spacer E selected from the carboxylic acid, amine and alcohol functions,

said substituted anionic compound comprising at least two carboxylic acid functions in the form of alkali metal salt salts selected from the group consisting of Na ⁺ and K *.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound corresponds to the following Formula I:

Formula I

in which :

R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 3 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions,

AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function,

E represents an at least divalent radical, comprising from 2 to 6 carbon atoms,

F, F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of the AA radical, F 'being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E,

p being an integer from 1 to 3,

m is an integer from 0 to 6; n is an integer from 0 to 6; m + n is an integer from 1 to 6;

said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na ⁺ and K ⁺ .

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least 2 carboxylic acid functions in the form of an alkali metal salt are carried by the radicals R, AA or E.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkali are carried by radicals R and E.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkali are carried by the radicals R and AA.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkaline are carried by the radicals AA and E.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkali are carried by the radical R, comprising 3 to 12 carbon atoms,.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkaline are carried by the radical AA.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkaline are carried by the radical E.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which, if m + n * p = 1, then R comprises at least one function carboxylic acid. * represents the mathematical sign multiplication.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which, E is an at least divalent radical, linear or branched alkyl.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which, E represents a linear or branched, saturated or unsaturated hydrocarbon radical comprising from 2 to 6 carbon atoms, optionally comprising at least one functional group chosen from alcohol and carboxylic acid functions,

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F is chosen from amide or carbamate functions.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F is an amide function.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which F is a carbamate function.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F 'is a urea function.

In one embodiment F 'is an amide function.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which F 'is a carbamate function.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F and F 'are chosen from amide or carbamate functions.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F and F 'are amide functions.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F and F 'are carbamate functions.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F "is a urea function.

In one embodiment F "is an amide function.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F "is a carbamate function. In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F 'is an amide function and F "is a carbamate function.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the anionic compound known as:

Formula I

in which :

R represents a hydrocarbon radical comprising from 3 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions,

AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having a free acid function,

E represents a radical comprising from 2 to 6 carbon atoms,

F, F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of a radical AA,

p being an integer from 1 to 3,

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radicals R, AA or E.

In one embodiment, the at least two carboxylic acid functional groups in the form of an alkali metal salt are carried by the radicals R and E. In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radicals R and AA.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radicals AA and E.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radical R, comprising 3 to 12 carbon atoms,

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radical AA.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radical E.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which E is an at least divalent radical, linear or branched alkyl.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which E represents a linear or branched, saturated or unsaturated hydrocarbon radical containing from 2 to 6 carbon atoms. , optionally comprising at least one functional group chosen from alcohol and carboxylic acid functions,

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the radical R may comprise from 4 to 10 carbon atoms, in particular from 4 to 6 atoms. of carbon.

The radical R, comprising 3 to 12 carbon atoms, may be a linear, branched or cyclic hydrocarbon radical, and may be saturated or unsaturated. In particular, the radical R, comprising 3 to 12 carbon atoms, is a saturated linear hydrocarbon radical. In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n = 6.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n = 5.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which m + n = 4.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n = 3.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n = 2.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n = 1.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when it is bisubstituted, is chosen from the compounds of formula I in which radical -R- is chosen from radicals comprising 3 to 12 carbon atoms,

in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and:

3 <r * t + q <12, a is 0 or 1, where the groups R _ql, _q2 R, R, R i and _R2 are, independently from each other selected from -H, -OH or - COOH; 2 <q + r * t <12, a is 0 or 1, where the groups R _ql, _q2 R, R _r and R _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH. 1 <q + r * t ≤ 12, a is equal to 0 or 1, when the groups R _qt , R _q2 , R _r i and R _r2 are, independently of one another, chosen from -H, -OH, or -COOH and at least two groups R _q or R _r are -COOH.

If a = 0 then t = 0. When q> 1 and / or t≥ 1, then the R _ql and R _q2 and R _ri and R _r2 are identical or different from one carbon to another.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in wherein the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV:

Form IV

3 ≤ q + r * t <12, a is 0 or 1, when _q R i, R _q2, R _r and R i _r2 are independently of each other, selected from -H, -OH or -COOH; 2 <q + r * t <12, a is 0 or 1, when the groups R _q1 , R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

1 ≤ q + r * t <12, a is 0 or 1, where the groups R _ql, _q2 R, R and R _rl _r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R _q or R _{r groups} are -COOH.

If a = 0 then t = 0. When q> 1 and / or t> 1, then the R _q1 and R _q2 and the R _rl and R _r2 are identical or different from one carbon to another.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in wherein the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV ": Formula IV "in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and:

2 <q + r * t <11, a is 0 or 1, when the groups R _q1 , R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH, - COOH; 1 <q + r * t <11, a is 0 or 1, when the groups R _q , R _q2 , R _r i and R _r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in wherein the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV ":

3 <r * t + q <12, a is 0 or 1, when _q R i, R _q2, _rl R and R _r2 are independently of each other, selected from -H, -OH or - COOH; 2 <q + r * t <12, a is 0 or 1, when the groups R _qi , R _q2 , R _ri and R _r2 are, independently of one another, selected from -H, -OH, or - COOH and at least one R _q or R _r is -COOH. 1 <q + r * T≤ 12, a is 0 or 1, where the groups R _ql, _q2 R, R _r and R i _r2 are independently of each other, selected from -H, -OH, or -COOH and at least two groups R _q or R _r are -COOH.

If a = 0 then t = 0. When q> 1 and / or t> 1, then the R _qi and R _q2 and the R _r and R _r2 are identical or different from one carbon to another.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the -R- radical, when bisubstituted, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV in which t = 0, a = 0 and r = 0, represented by formula V:

in which :

q is an integer between 3 and 12, when the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH, -COOH;

- q is an integer between 2 and 12, when the R i groups and R _q _q2 are independently from each other selected from -H, -OH and -COOH and at least one Rq is -COOH.

q is an integer between 1 and 12, when the groups R _q1 and R _q2 are, independently of each other, chosen from -H, -OH and -COOH and at least two R _q are -COOH.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the -R- radical, when monosubstituted, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV in which t = 0, a = 0 and r = 0, represented by formula V:

in which ; q is an integer between 3 and 12, when the groups _{q 1} and R _{q 2} are, independently of one another, chosen from -H, -OH, -COOH;

- q is an integer between 2 and 12, when the groups R _qi and R _q2 are, independently of each other, selected from -H, -OH and -COOH and at least one Rq is a -COOH.

- q is an integer between 1 and 12, where R _q] and _q2 R groups are independently from each other selected from -H, -OH and -COOH, and at least two R _q are -COOH .

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the -R- radical, when monosubstituted, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV in which t = 0, a = 0 and r = 0, represented by the formula V ":

Formula V "

in which :

- q is an integer between 2 and 11, when the R _qi and _q2 R groups are independently from each other selected from -H, -OH, -COOH;

q is an integer between 1 and 11, when the groups R _q1 and R _q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one R _q is a -COOH.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the -R- radical, when monosubstituted, is chosen from the radicals, comprising 3 to 12 carbon atoms of formula IV in which t = 0, a = 0 and r = 0, represented by formula V "

Formula V

in which : - q is an integer between 3 and 12, when the groups R i and R _q2 _q are independently of each other, selected from -H, -OH, -COOH;

q is an integer between 2 and 12, when the groups R _qi and R _q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one R _q is a -COOH.

q is an integer between 1 and 12, when the groups R _q1 and R _q2 are, independently of each other, chosen from -H, -OH and -COOH and at least two R _q are -COOH. In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound is chosen from the compounds of formula I in which the radical -R- is a radical derived from a compound comprising 3 to 12 + (m + n) carbon atoms.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound is chosen from the compounds of formula I in which m + n = 6 and the radical -R- is a radical derived from a compound comprising 3 to 18 carbon atoms.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound is chosen from the compounds of formula I in which m + n = 4 and the radical -R- is a radical derived from a compound comprising 3 to 16 carbon atoms.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound is chosen from the compounds of formula I in which m + n = 2 and the radical -R-, comprising 3 to 12 carbon atoms, is a radical derived from a compound comprising 3 to 14 carbon atoms, of formula VI:

Form VI In which, q and r are integers between 0 and 12, the groups R _q i, R _q 2, R 1 and Rr 2 are, independently of each other, chosen from -H, -OH, -COOH,

-X and -Y are the same or different reactive functions that react with the precursor of E or AA to form F 'or F, respectively, and are selected from -COOH, -OH, -IMH2,

- a is 0 or 1, and

- 3 <q + r * t <12, when all X, Y, Rqi, Rq2, Rn and Rr2 are different from - COOH,

- 2 <q + r * t <11, when at least one of X, Y, R _q i, R _q 2, R 1 and Rr 2 is -COOH, and if it is X or Y then it does not is not involved in a function F or F ',

-1 <q + r * t <11, when at least two of X, Y, Rqi, Rq2, Rri and Rr2 are -COOH, and if it is X or Y then it is not involved in a function F or F ',

If a = 0 then t = 0. When q> 1 and / or t> 1, then the R _q i and R _q 2 and R _r i and Rr 2 are the same or different from one carbon to another.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound is chosen from the compounds of formula I in which m + n = 1 and the radical -R-, comprising 3 to 12 carbon atoms, is a radical derived from a compound comprising 3 to 13 carbon atoms, of formula VI above and if -X or -Y is -NH2 then it is is the group that reacts with the precursor of E or AA to form F 'or F.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is a radical derived from a compound of formula VI, wherein t = 0, a = 0 and r = 0, represented by formula VII:

Wherein R _q i and R _q Σ are, independently of one another, selected from -H, -OH, -COOH,

FIRE I LLE OF REM PLACEM ENT (RULE 26) - 3≤ q <12, when all X, Y, R _q i, R _q2 are different from -COOH,

- 2 <q <11, when at least one of X, Y, R _q1 , R _q2 is -COOH, and if it is X or Y then it is not involved in a function F or F ' ,

-1 <q <11, when at least two of X, Y, R _q1 , R _q2 is -COOH, and if it is X or Y then it is not involved in a function F or F ',

[00091] -X and -Y are the reactive functions which react with the precursor of E or AA to form F 'or F, respectively. In one embodiment, the substituted anionic compound is chosen from compounds of formula In which m + n = 1 and the radical -R- is a radical derived from a compound comprising 3 to 13 carbon atoms, of formula VI above and if -X or -Y is -NH ₂ then it is is the group that reacts with the precursor of E or AA to form F 'or F.

In one embodiment, the precursor of R is chosen from the precursors of formula VI or VII in which -X and -Y, identical or different, are chosen from -COOH, -OH. The radical R, comprising 3 to 12 carbon atoms, may comprise at least one function, in particular chosen from alcohol and carboxylic acid functions.

According to one embodiment, the radical R, comprising 3 to 12 carbon atoms, comprises o carboxylic acid functions, o being an integer between 1 and 3, in particular o being equal to 1 or 2, and in particular o is 1.

According to another embodiment, the radical R, comprising 3 to 12 carbon atoms, is devoid of carboxylic acid functions.

According to one embodiment, the radical R, comprising 3 to 12 carbon atoms, comprises at least one alcohol function, in particular it comprises from 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions.

According to another embodiment, the radical R, comprising 3 to 12 carbon atoms, is devoid of alcohol function.

According to one embodiment, the radical R, comprising 3 to 12 carbon atoms, comprises 1 or 2 alcohol functions and 1 carboxylic acid function.

The radical R, comprising 3 to 12 carbon atoms, may come from a polycarboxylic acid, especially a dicarboxylic acid.

According to one embodiment, all the carboxylic acid functions of the polycarboxylic acid are involved in the functions F and F '. Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are involved in the functions F and F '.

According to another embodiment, all the carboxylic acid functions of the polycarboxylic acid are not involved in the functions F and F '.

[000104] Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are not involved in the F and F 'functions.

In particular, 1 or 2 carboxylic acid functions are not involved in the functions F and F ', especially 1 carboxylic acid function is not involved in the functions F and F'.

The radical R, comprising 3 to 12 carbon atoms, may be derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, pentanedioic acid, hexanedioic acid (or adipic acid), heptanedioic acid, octanedioic acid, nonanedioic acid, butenedioic acid, pentenedioic acid, and hexadienedioic acid.

In particular, the radical R, comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, and acid. pentanedioic acid and hexanedioic acid (or adipic acid).

Even more particularly, the radical R, comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid) or tartaric acid.

The radical R, comprising 3 to 12 carbon atoms, may be derived from an amino acid.

In particular, the radical R, comprising 3 to 12 carbon atoms, may be derived from an amino acid selected from glutamic acid and aspartic acid.

The radical R, comprising 3 to 12 carbon atoms, may be derived from a diol. The diol may be chosen from diethylene glycol, triethylene glycol and tetraethylene glycol, propane diol, butanediol, pentanediol, hexanediol, heptane diol and octane diol.

In particular, the radical R, comprising 3 to 12 carbon atoms, of the substituted anionic compound is derived from a dicarboxylic acid, an amino acid or a diol.

The AA radical is derived from an aromatic amino acid comprising a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative.

FIRE I LLE OF REM PLACEM ENT (RULE 26) having substituted or unsubstituted phenyl or indole. In particular, the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.

The radical AA is linked to the radical E or the radical R by a function F or F "involving the amine of the aromatic amino acid or an aromatic amino acid derivative.

By "aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole" is meant a compound comprising from 7 to 20 carbon atoms, a substituted or unsubstituted phenyl or indole, an amine function and a functional group. acid.

By "aromatic amino acid derivative" is meant the decarboxylated derivatives, amino-alcohol derivatives, or amino-amides corresponding to aromatic amino acids having a phenyl or a substituted or unsubstituted indole. The derivatives of said aromatic amino acids comprising a substituted or unsubstituted phenyl or indole may in particular be chosen from amino-alcohols and amino-amides.

According to one embodiment AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids. The aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.

According to one embodiment, the aromatic amino acid comprising a phenyl or an indole, substituted or unsubstituted, is a natural amino acid, especially chosen from phenylalanine, tyrosine and tryptophan, especially phenylalanine.

[000119] The aromatic amino acids comprising a phenyl or a substituted or unsubstituted indole and their derivatives may, where appropriate, be in laevorotatory, dextrorotatory or racemic form. In particular they are in laevorotic form.

[000120] According to one embodiment, the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the radical E is derived from a linear or branched alkyl compound comprising at least two functions chosen from the group consisting of -OH, -COOH, -NH ₂ . In particular, the radical E is derived from a compound comprising from 2 to 6 carbon atoms, and optionally comprising 1 or 2 carboxylic acid functions and / or 1, 2 or 3 alcohol functions.

The radical E is a radical at least divalent, in particular divalent, trivalent or tetravalent.

According to one embodiment, the radical E is derived from a linear or branched alkyl compound, optionally carrying one or two carboxylic acid functions.

The radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3. propanediol or TRIS, serinol, and threoninol.

According to one embodiment, when the radical E is derived from an amino-diol or an amino-triol, it is respectively substituted with 2 or 3 AA radicals.

According to another embodiment, the radical E may be derived from an amino acid comprising two carboxylic acid functions, in particular aspartic acid or glutamic acid. In this embodiment, the radical E can be linked to one or two AA radicals.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E does not comprise an -NH 2 function.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the radical E is different from the radical R.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E is different from the precursor of the radical R.

According to one embodiment, the composition according to the invention is characterized in that the substituted anionic compound comprises from 2 to 8, in particular from 2 to 6, or even from 2 to 4 carboxylic acid functions.

In one embodiment, the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n * p = 1.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n * p = 2.

FIRE I LLE OF REM PLACEM ENT (RULE 26) In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n * p = 3.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n * p = 4.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n * p = 5.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m + n * p = 6.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which m + n * p = 7.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which, m + n * p = 8,

[000140] The calculation m + n * p gives the number of carboxylate functions provided by AA. When the radical R, comprising 3 to 12 carbon atoms, comprises free carboxylate functions, then the total number of free carboxylate functions is greater than m + n * p.

According to one embodiment, the substituted anionic compound does not comprise an AA radical bonded via a spacer E. Thus, the substituted anionic compound can correspond to Formula I in which n = 0.

In one embodiment, the composition is characterized in that the substituted anionic compound does not comprise an AA radical bonded via a spacer E, the substituted anionic compound can correspond to formula I in which n = 0 and corresponds to formula II:

AT Formula II

AA, F and R have the definitions given above,

1 <m <6.

FIRE I LLE OF REM PLACEM ENT (RULE 26) In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula II in which m = 1:

AA

\ F R Form VIII

AA, F and R have the definitions given above,

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula II in which m = 2:

AA, F and R have the definitions given above,

According to one embodiment, the substituted anionic compound does not comprise an AA radical bonded via the F function to the radical R. Thus, the substituted anionic compound can correspond to Formula I in which m = 0.

In one embodiment, the composition is characterized in that the substituted anionic compound does not comprise an AA radical bonded via the F function to the radical R, the substituted anionic compound may correspond to Formula I in which m = 0. and corresponds to formula III:

Formula III

AA, E, F ', F ", p and R are as defined above,

1 <n <6.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula III in which n = 1: Formula X

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula III in which n = 2: Form XI

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula III, X or XI in which p = 1.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula III, X or XI in which p = 2.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula III, X or XI in which p = 3.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula III or X in which n = 1 and p = 3.

In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the anionic compounds of formula III or XI in which n = 2 and p = 3

According to one embodiment, the substituted anionic compound corresponds to Formula I in which the radical AA is derived from phenylalanine, and the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid, succinic acid or an amino acid selected from aspartic acid and glutamic acid, especially the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid or succinic acid and n = 0 and m = 1.

According to one embodiment, the substituted anionic compound corresponds to Formula I in which the radical AA is derived from phenylalanine, and the radical R, comprising 3 to 12 carbon atoms, is derived from succinic acid, tartaric acid or an amino acid selected from aspartic acid and glutamic acid, n =

0 and m = 1.

According to one embodiment, the substituted anionic compound corresponds to Formula I in which the radical AA is derived from phenylalanine, n = 0, m = 1, the radical R, comprising 3 to 12 carbon atoms, is from tartaric acid or succinic acid, in particular tartaric acid, and carries an acid function.

According to one embodiment, the substituted anionic compound corresponds to Formula I in which the AA radical is derived from phenylalanine, m = 0, n = 1, p = 3, and E is derived from TRIS. In particular the radical R, comprising 3 to 12 atoms of carbon, is derived from tartaric or succinic acid and comprises an acid function where R is a radical derived from a diol.

According to one embodiment, the substituted anionic compound corresponds to Formula I in which the AA radical is derived from phenylalanine, m = 0, n = 1, p = 2, and E is derived from aspartic acid. or glutamic acid. In particular, the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric or succinic acid and comprises an acid function or the radical R, comprising 3 to 12 carbon atoms, is a radical derived from a diol.

According to one embodiment, the substituted anionic compound corresponds to Formula I in which the AA radical is derived from phenylalanine, m = 0, n = 1, 2 or 3, in particular n = 3, p = 2, and E is derived from aspartic acid or glutamic acid and the radical R, comprising 3 to 12 carbon atoms, is derived from glutamic acid.

According to one embodiment, the substituted anionic compound corresponds to Formula I in which the AA radical is derived from phenylalanine, m = 0, n = 1, in particular n = 1, p = 2, and E is derived from aspartic acid or glutamic acid and the radical R, comprising 3 to 12 carbon atoms, is derived from aspartic acid.

[000161]

[000162] In particular, the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from succinic acid and comprises a carboxylic acid, m = 0, n = 1, p = 3, E is derived from TRIS, F 'is an amide function, the AA radical is derived from phenylalanine, and F "is a carbamate function.

[000163] In particular, the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from succinic acid and comprises a carboxylic acid, m = 0, n = 1, p = 3, E is derived from TRIS, F 'is an amide function, the AA radical is derived from phenylalanine, and F "is a urea function. [...] In particular, the substituted anionic compound corresponds to Formula I in wherein the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid and comprises a carboxylic acid, m = 1, n = 0, F is an amide function, and the AA radical is derived from phenylalanine.

In particular, the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from succinic acid and comprises a carboxylic acid, m = 1, n = 0, F is an amide function, and the AA radical is derived from phenylalanine.

FIRE I LLE OF REM PLACEM ENT (RULE 26) In particular, the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid and comprises a carboxylic acid, m = 0, n = 1, p = 3, E is derived from TRIS, F 'is an amide function, the AA radical is derived from phenylalanine, and F "is a carbamate function.

[000167] In particular, the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid and comprises a carboxylic acid, m = 0, n = 1, p = 2, E is derived from aspartic acid, F 'is an amide function, the AA radical is derived from phenylalanine, and F "is an amide function.

In one embodiment, the composition is characterized in that the molar ratios of substituted anionic compound / insulin are between 0.6 and 300.

In one embodiment, the composition is characterized in that the molar ratios of substituted anionic compound / insulin are between 0.6 and 120.

In one embodiment, the composition is characterized in that the molar ratios substituted anionic compound / insulin are between 0.7 and 80.

In one embodiment, the composition is characterized in that the molar ratios of substituted anionic compound / insulin are from 1.4 to 60.

In one embodiment, the composition is characterized in that the molar ratios of substituted anionic compound / insulin are between 1.9 and 40.

In one embodiment, the composition is characterized in that the molar ratios substituted anionic compound / insulin are between 2.3 and 40.

In one embodiment, the composition is characterized in that the molar ratio of substituted anionic compound / insulin is equal to 8, 12 or 16.

In the molar ratios above, the number of moles of insulin is understood as the number of moles of insulin monomer.

In one embodiment, the composition is characterized in that the weight ratios substituted anionic compound / insulin are between 0.5 and 30.

In one embodiment, the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 0.5 and 20.

In one embodiment, the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 0.5 and 10.

In one embodiment, the composition is characterized in that the weight ratios substituted anionic compound / insulin are between 0.6 and 7.

In one embodiment, the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 1.2 and 5.

FIRE I LLE OF REM PLACEM ENT (RULE 26) In one embodiment, the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 1.6 and 4.

In one embodiment, the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 2 and 4.

In one embodiment, the composition is characterized in that the weight ratio substituted anionic compound / insulin is 2, 3, 4 or 6.

In one embodiment, the composition is characterized in that the insulin is human insulin.

By human insulin is meant insulin obtained by synthesis or recombination whose peptide sequence is the sequence of human insulin, including allelic variations and homologues.

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

In one embodiment, the composition is characterized in that the insulin is a similar insulin.

By insulin analog is meant a recombinant insulin whose primary sequence contains at least one modification with respect to the primary sequence of human insulin.

[000189] In one embodiment the insulin analogue is selected from the group consisting of insulin lispro (Humalog ^®), insulin aspart (Novolog ^®, Novorapid ^®) and insulin glulisine (Apidra).

In one embodiment, the composition is characterized in that the insulin analog is insulin lispro (Humalog ^® ).

In one embodiment, the composition is characterized in that the insulin analogue is insulin aspart (Novolog®, Novorapid®).

In one embodiment, the composition is characterized in that the insulin analog is insulin glulisine (Apidra ^® ).

[000193] In one embodiment, the composition is characterized in that the insulin is in hexameric form.

In one embodiment, the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 240 and 3000 μΜ (40 to 500 IU / ml).

In one embodiment, the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 3000 μΜ (100 to 500 IU / ml).

FIRE I LLE OF REM PLACEM ENT (RULE 26) In one embodiment, the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 2400 μΜ (100 to 400 IU / mL).

In one embodiment, the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 1800 μΜ (100 to 300 IU / ml).

In one embodiment, the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 1200 μΜ (100 to 200 IU / ml).

[000199] In one embodiment, the composition is characterized in that it relates to a pharmaceutical composition characterized in that the insulin concentration is 600 μΜ (100 IU / ml), 1200 μΜ (200 IU / ml), 1800 μΜ (300 IU / mL), 2400 μM (400 IU / mL) or 3000 μM (500 IU / mL).

In one embodiment, the composition is characterized in that the polyanionic compound has an affinity for zinc lower than the affinity of insulin for zinc and a dissociation constant Kdca = [PNP compound] ^{1 "} [Ca ^2+] 7 [(compound PNP) _r - (Ca ²⁺⁾ _i] is less than or equal to 10 ^l ^'5.

[000201] This dissociation constant is the reaction constant associated with the dissociation of the complex (PNP compound) _r - (Ca ²⁺ ) _s , that is to say at the following reaction: (PNP compound) r- ( Ca ²⁺ ) _s r (PNP compound) + sCa ²⁺ .

[000202] The dissociation constants (Kd) of the various polyanionic compounds with respect to the calcium ions are determined by external calibration using a specific electrode for Calcium ions (Mettler Toledo) and a reference electrode. All measurements are carried out in 150 mM NaCl at pH 7. Only the concentrations of free calcium ions are determined; the calcium ions bound to the polyanionic compound do not induce electrode potential.

In one embodiment, the composition is characterized in that the polyanionic compound is selected from the group consisting of polycarboxylic acids and their Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

[000204] In one embodiment, the composition is characterized in that the polyanionic compound is an anionic molecule.

SUBSTITUTE SHEET (RULE 26) In one embodiment, the composition is characterized in that the anionic molecule is selected from the group consisting of citric acid, aspartic acid, glutamic acid, malic acid and tartaric acid. succinic acid, adipic acid, oxalic acid, phosphate, polyphosphoric acids, such as triphosphate and their salts of Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ .

In one embodiment, the composition is characterized in that the anionic molecule is citric acid and its salts of Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ . In one embodiment, the composition is characterized in that the polyanionic compound is chosen from anionic compounds consisting of a saccharide skeleton formed of a discrete number u of between 1 and 8 (1 <u <8). saccharide units, said saccharide units being selected from the group consisting of hexoses, cyclic form or open reduced form, identical or different, linked by identical or different glycosidic linkages substituted by carboxyl groups, and their salts.

In one embodiment, the composition is characterized in that the polyanionic compound consisting of a saccharide skeleton formed by a discrete number of saccharide units is obtained from a disaccharide compound selected from the group consisting of trehalose, maltose, lactose, sucrose, cellobiose, isomaltose, maltitol and isomaltitol.

In one embodiment, the composition is characterized in that the polyanionic compound consisting of a saccharide backbone formed by a discrete number of saccharide units is obtained from a compound consisting of a skeleton formed of a discrete number of saccharide units selected from the group consisting of maltotriose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, maltooctaose and iso maltotriose

In one embodiment, the composition is characterized in that the polyanionic compound consisting of a saccharide skeleton formed by a discrete number of saccharide units is chosen from the group consisting of carboxymethylmaltotriose, carboxymethylmaltotetraose and carboxymethylmaltopentaose. carboxymethyl maltohexaose, carboxymethylmaltoheptaose, carboxymethylmaltooactose and carboxymethylisomaltotriose.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 100 mg / mL. 3

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 50 mg / ml.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 36 mg / mL.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 36.5 mg / mL.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 2.1 and 25 mg / mL.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 4.2 and 18 mg / ml.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 5.6 and 15 mg / ml.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is between 7 and 15 mg / ml.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is 7.3 mg / mL.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is 10.5 mg / ml.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is 14.6 mg / mL.

In one embodiment, the composition is characterized in that the concentration of substituted anionic compound is 21.9 mg / mL.

[000223] In one embodiment, the composition is characterized in that the polyanionic compound concentration is between 2 and 150 mM.

[000224] In one embodiment, the composition is characterized in that the polyanionic compound concentration is between 2 and 100 mM.

[000225] In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 2 and 75 mM.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 2 and 50 mM.

[000227] In one embodiment, the composition is characterized in that the polyanionic compound concentration is between 2 and 30 mM.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 2 and 20 mM.

[000229] In one embodiment, the composition is characterized in that the polyanionic compound concentration is between 2 and 10 mM.

FIRE I LLE OF REM PLACEM ENT (RULE 26) In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 5 and 150 mM.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 5 and 100 mM.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 5 and 75 mM.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 5 and 50 mM.

[000234] In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 5 and 30 mM.

[000235] In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 5 and 20 mM.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 5 and 10 mM.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 30 mg / mL.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 25 mg / mL.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 10 mg / ml.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 8 mg / ml.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 1 and 30 mg / ml. In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 1.5 and 25 mg / ml.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 2 and 25 mg / ml.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 2 and 10 mg / ml.

In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 2 and 8 mg / ml.

FIRE I LLE OF REM PLACEM ENT (RULE 26) In one embodiment, the composition is characterized in that the pH of the composition is between 6 and 8.

In a particular embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound as defined above, and citric acid or its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts, in particular as defined above.

In a particular embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula I as defined above, and citric acid or its salts of Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ , especially as defined above.

In a particular embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula III as defined above, and citric acid or its salts of Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ , especially as defined above.

In a particular embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula IV as defined above, and citric acid or its salts of Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ , especially as defined above.

It is known to those skilled in the art that the time of action of insulins is dependent on the insulin concentration. Only the action time values of the compositions at 100 IU / ml are documented.

[000252] The "regular" human insulin compositions on the market at a concentration of 600 μΜ (100 IU / ml) have an action time of between 50 and 90 minutes and an end of action of about 360 to 420 minutes in humans. The time to reach the maximum insulin concentration in the blood is between 90 and 180 minutes in humans.

[000253] The fast analogous insulin compositions on the market at a concentration of 600 μΜ (100 IU / ml) have an action time of between 30 and 60 minutes and an end of action of approximately 240-300 minutes. in humans. The time to reach the maximum insulin concentration in the blood is between 50 and 90 minutes in humans. [000254] The invention also relates to a method for preparing a human insulin composition having an insulin concentration of between 240 and 3000 μΜ (40 and 500 IU / ml), the action time of which in humans is lower than that of the reference composition at the same insulin concentration in the absence

FIRE I LLE OF REM PLACEM ENT (RULE 26) substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition of at least one least one polyanionic compound.

[000255] In one embodiment, the composition is characterized in that the insulin is in hexameric form.

In one embodiment, the composition is characterized in that the pH of the composition is between 6 and 8.

[000257] The invention also relates to a method for preparing a human insulin composition having an insulin concentration of between 600 and 1200 μΜ (100 and 200 IU / ml), the action time of which in humans is lower than that of the reference composition at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000258] In one embodiment of the method, the insulin is in hexameric form.

In one embodiment of the method, the pH of the composition is between 6 and 8.

[000260] The invention also relates to a method for preparing a human insulin composition having an insulin concentration of 600 μΜ (100 IU / ml), whose action time in humans is less than 60 minutes characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000261] In one embodiment of the method, the insulin is in hexameric form.

In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing a human insulin composition having an insulin concentration of 1200 μΜ (200 IU / ml), the action time of which in humans is less than 10% less than that of the composition of human insulin at the same concentration (200 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000264] In one embodiment of the method, the insulin is in hexameric form.

In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing a human insulin composition having an insulin concentration of 1800 μΜ (300 IU / ml), the action time of which in humans is less than 10% less than that of the composition of human insulin at the same concentration (300 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000267] In one embodiment of the method, the insulin is in hexameric form.

In one embodiment of the method, the pH of the composition is between 6 and 8.

[000269] The invention also relates to a method for preparing a human insulin composition having an insulin concentration of 2400 μΜ (400 IU / ml), whose action time in humans is less than 10% less than that of the composition of human insulin at the same concentration (400 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000270] In one embodiment of the method, the insulin is in hexameric form.

In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing a human insulin composition having an insulin concentration of 3000 μΜ (500 IU / ml), the action time of which in humans is less than minus 10% to that of the composition of human insulin at the same concentration (500 IU / mL) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000273] In one embodiment of the method, the insulin is in hexameric form.

[000274] In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention consists in the preparation of a so-called rapid human insulin composition characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) ) a step of adding to said composition at least one polyanionic compound.

In one embodiment, the insulin is in hexameric form.

In one embodiment, the pH of the composition is between 6 and 8.

[000278] The invention also relates to a method for preparing a human insulin composition at a concentration of 600 μΜ (100 IU / ml) whose action time in humans is less than 60 minutes, preferably less than 45 minutes, and even more preferably less than 30 minutes, characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of addition to said composition of at least one polyanionic compound.

[000279] In one embodiment of the method, the insulin is in hexameric form.

[000280] In one embodiment of the method, the pH of the composition is between 6 and 8.

[000281] The invention also relates to a method for preparing a similar insulin composition having an insulin concentration of between 240 and 3000 μΜ (40 and 500 IU / ml), the action time of which in humans is lower than that of the reference composition at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000282] In one embodiment of the method, the insulin is in hexameric form.

FIRE I LLE OF REM PLACEM ENT (RULE 26) [000283] In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing a similar insulin composition having an insulin concentration of between 600 and 1200 μΜ (100 and 200 IU / ml), the action time of which in humans is lower than that of the reference composition at the same concentration of insulin analog in the absence of substituted anionic compound substituted anionic compound and polyanionic compound, characterized in that it comprises (1) a step of addition to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000285] In one embodiment of the method, the insulin is in hexameric form.

[000286] In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 600 μΓηοΙ / L (100 IU / mL), the action time of which in humans is less than 30 minutes, characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.

[000288] In one embodiment of the method, the insulin is in hexameric form.

[000289] In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 1200 μΜ (200 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.

[000291] In one embodiment of the method, the insulin is in hexameric form.

[000292] In one embodiment of the method, the pH of the composition is between 6 and 8.

FIRE I LLE OF REM PLACEM ENT (RULE 26) [000293] The invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 1800 μΜ (300 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.

[000294] In one embodiment of the method, the insulin is in hexameric form.

[000295] In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing an insulin-like composition having an insulin concentration of 2400 μΜ (400 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.

[000297] In one embodiment of the method, the insulin is in hexameric form.

[000298] In one embodiment of the method, the pH of the composition is between 6 and 8.

The invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 3000 μΜ (500 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.

In one embodiment of the method, the insulin is in hexameric form.

[000301] In one embodiment of the method, the pH of the composition is between 6 and 8.

FIRE I LLE OF REM PLACEM ENT (RULE 26) The invention consists in the preparation of a so-called fast-acting analog insulin composition characterized in that it comprises a step of adding to said composition at least one substituted anionic compound, said compound comprising groups partially substituted carboxyl functional groups, unsubstituted carboxyl-functional groups being salifiable

In one embodiment, the preparation further comprises a step of adding to said composition at least one polyanionic compound.

[000304] In one embodiment, the insulin is in hexameric form.

In one embodiment, the pH of the composition is between 6 and 8.

[000306] In one embodiment, the invention relates to the use of at least one substituted anionic compound, in combination with a polyanionic compound, to prepare a pharmaceutical composition of human insulin, which, after administration, makes it possible to accelerate the passage of human insulin into the blood and to reduce blood glucose more quickly compared to a composition free of substituted anionic compound.

In one embodiment, the invention relates to the use of at least one substituted anionic compound, in combination with a polyanionic compound, to prepare a similar insulin composition, allowing, after administration, to accelerate passage of the insulin analogue into the blood and to reduce blood glucose more rapidly compared to a composition free of substituted anionic compound.

[000308] In one embodiment of the use, the pH of the composition is between 6 and 8.

[000309] The invention also relates to a pharmaceutical composition according to the invention, characterized in that it is obtained by drying and / or lyophilization.

In one embodiment, the compositions according to the invention also comprise the addition of zinc salts at a concentration of between 0 and 500 μ, in particular between 0 and 300 μΜ, and in particular between 0 and 200 μΜ. .

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

0 and 50 mM, or between 15 and 50 mM.

[000312] In one embodiment the buffer is Tris.

In one embodiment, the compositions according to the invention further comprise preservatives. In one embodiment, the preservatives are selected from the group consisting of m-cresol and phenol alone or in admixture.

In one embodiment, the concentration of preservatives is between 10 and 50 mM, especially between 10 and 40 mM.

The compositions according to the invention may further comprise additives such as tonicity agents such as glycerine, sodium chloride (NaCl), mannitol and glycine.

The compositions according to the invention may further comprise additives according to the pharmacopoeia such as surfactants, for example polysorbate.

[000318] The compositions according to the invention may furthermore comprise all excipients compatible with the pharmacopoeia and compatible with the insulins used at the concentrations of use.

In the case of local and systemic releases, the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular. In particular, the mode of administration is the subcutaneous route.

[000320] The transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.

The invention also relates to the use of a composition according to the invention for the composition of a human insulin solution or the like of a concentration of 100 IU / ml or 200 IU / ml intended for implantable insulin pumps. or transportable.

According to another of its aspects, the invention also relates to the substituted anionic compounds as defined above.

In one embodiment, the substituted anionic compound corresponds to the following Formula I:

Formula I

in which :

R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical containing from 3 to 12 carbon atoms, comprising at least one functional group chosen from ether and alcohol functions, and possibly comprising a carboxylic acid function, AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function, - E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms,

F, F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of a AA radical, F 'being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E, p being an integer between 1 and 3,

said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na ⁺ and K ⁺ ,

excluding compounds in which m = 2 and n = 0 and R carrying a carboxylic acid function and an alcohol function [000324] In one embodiment the at least 2 carboxylic acid functions in the form of an alkali metal salt are borne by radicals R, AA or E.

In one embodiment, the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the radicals R and E.

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radicals R and AA.

In one embodiment, the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the AA and E radicals.

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radical R, comprising 3 to 12 carbon atoms.

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the AA radical.

In one embodiment, the at least two carboxylic acid functional groups in the form of an alkali metal salt are carried by the radical E.

In one embodiment, if m + n * p = 1, then R comprises at least one carboxylic acid function. * represents the mathematical sign multiplication. In one embodiment, F is chosen from amide or carbamate functions.

[000333] In one embodiment, F is an amide function.

[000334] In one embodiment, F is a carbamate function.

[000335] In one embodiment, F 'is a urea function.

In one embodiment F 'is an amide function.

[000337] In one embodiment, F 'is a carbamate function.

In one embodiment, F and F 'are chosen from amide or carbamate functions.

[000339] In one embodiment, F and F 'are amide functions.

[000340] In one embodiment, F and F 'are carbamate functions.

[000341] In one embodiment, F "is a urea function.

[000342] In one embodiment F "is an amide function.

[000343] In one embodiment, F "is a carbamate function.

In one embodiment, F 'is an amide function and F "is a carbamate function.

The radical R, comprising 3 to 12 carbon atoms, may be a linear, branched or cyclic hydrocarbon radical, and may be saturated or unsaturated. In particular the radical R is a saturated linear hydrocarbon radical.

[000346] In one embodiment, m + n = 6.

[000347] In one embodiment, m + n = 5.

[000348] In one embodiment, m + n = 4.

[000349] In one embodiment, m + n = 3.

[000350] In one embodiment, m + n = 2.

[000351] In one embodiment, m + n = 1.

In one embodiment, the substituted anionic compound, when bisubstituted, is chosen from the compounds of formula I in which the radical -R- is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV, comprising at least one function chosen from ether and alcohol functions:

Form IV

in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and: 3 <q + r * t <12, a is 0 or 1, when the groups R _q1 , R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH or - COOH; 2 <q + r * t <12, a is 0 or 1, when the groups RR _q2 , R _r i and R _r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

1 <q + r * t <12, a is equal to 0 or 1, when the groups RR _q2 , R _r i and R _r2 are, independently of one another, chosen from -H, -OH, or -COOH and at least two groups R _q or R _r are -COOH.

[000353] In one embodiment, a is equal to 1.

In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV, comprising at least one function selected from the ether functions

Form IV

3 <r * t + q <12, a is 0 or 1 when R _ql, _q2 R, R and R _rl _r2 are independently of each other, selected from -H, -OH or -COOH ; 2 q + r * t <12, a is 0 or 1, when _q R i, R _q2, _rl R and R _r2 are independently of each other, selected from -H, -OH, or - COOH and at least one R _q or R _r is -COOH.

1 <q + r * t <12, a is 0 or 1 when R _qi, R _q2, _rl R and R _r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R _q or R _{r groups} are -COOH.

[000355] In one embodiment, a is equal to 1. In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV ", comprising at least one functional group chosen from ether and alcohol functions:

2 <q + r * t <11, a is equal to 0 or 1, when the groups R _q i, R _q2 , R _r i and R _r2 are, independently of one another, chosen from -H, -OH, -COOH;

1 <q + r ≤ 11 * t, a is 0 or 1, where the groups R _qlj R _q2, R _r and R i _r2 are independently of each other, selected from -H, -OH, or - COOH and at least one R _q or R _r is -COOH.

If a = 0 then t = 0. When q> 1 and / or t> 1, then the R _qi and R _q2 and the R _rl and R _r2 are identical or different from one carbon to another.

[000357] In one embodiment, a is equal to 1.

In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from compounds of formula I in which the radical -R- comprising 3 to 12 carbon atoms is chosen from radicals comprising 3. to 12 carbon atoms of formula IV ", comprising at least one function selected from the functions

Formula IV "in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and: 3 <q + r * t <12, a is 0 or 1, when the groups R _q1 , R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH or - COOH; 2 <q + r * t <12, a is 0 or 1, when the groups R _q1, R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

1 <q + r * T≤ 12, a is 0 or 1, when _q R i, R _q2, R _r and R i _r2 are independently of each other, selected from -H, -OH, or -COOH and at least two R _q or R _{r groups} are -COOH.

[000359] In one embodiment, a is equal to 1.

In one embodiment, the -R- radical, when bisubstituted, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , represented by formula V, comprising at least one alcohol function:

in which :

q is an integer between 3 and 12, when the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH, and COOH,

- q is an integer between 2 and 12, when the R _gl and _q2 R groups are independently from each other selected from -H, -OH and -COOH and at least one R _q is -COOH,

q is an integer between 1 and 12, when the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R _q are -COOH and at least one R _q1 or R _q2 is -OH.

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , represented by formula V, comprising at least one alcohol function:

in which :

- q is an integer between 3 and 12, when the R _qi and _q2 R groups are independently from each other selected from -H, -OH, and -COOH

- q is an integer between 2 and 12, when the groups R _q and R _q2 are independently from each other selected from -H, -OH and -COOH and at least one Rq is -COOH,

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , represented by formula V ", comprising at least one alcohol function:

in which :

- q is an integer between 2 and 11, when the groups R i and R _q2 _q are independently of each other, selected from -H, -OH, and -COOH

- q is an integer between 1 and 11, when the groups R i and R _q2 _q are, independently from each other selected from -H, -OH and -COOH and at least one R _q is -COOH and at least one R _q1 or R _q2 is -OH.

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals, comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0, represented by the formula V ": Formula V "

in which :

- q is an integer between 3 and 12, when the R _qi and _q2 R groups are independently from each other selected from -H, -OH, and -COOH,

q is an integer between 2 and 12, when the groups R _q1 and R _q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one R _q is a -COOH,

q is an integer between 1 and 12, when the groups R _qi and R _q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R _q are -COOH and at least one R _q1 or R _q2 is -OH.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the radical -R- is a radical derived from a compound comprising 3 to 12 + (m + n) carbon atoms.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 6 and the radical -R- is a radical derived from a compound comprising 3 to 18 carbon atoms.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 4 and the radical -R- is a radical derived from a compound comprising 3 to 16 carbon atoms.

[000367]

[000369] According to another embodiment, the radical R, comprising 3 to 12 carbon atoms, is free of carboxylic acid functions.

[000370] According to one embodiment, the radical R, comprising 3 to 12 carbon atoms, comprises 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions.

The radical R, comprising 3 to 12 carbon atoms, can come from a polycarboxylic acid, especially a dicarboxylic acid. According to one embodiment, all the carboxylic acid functions of the polyoxycarboxylic acid are involved in the functions F and F '.

[000374] Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are involved in the functions F and F '.

[000375] According to another embodiment, all the carboxylic acid functions of the polyoxycarboxylic acid are not involved in the functions F and F '.

[000376] Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are not involved in the F and F 'functions.

In particular, the radical R, comprising 3 to 12 carbon atoms, is derived from malic acid or tartaric acid.

In particular, the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid.

In particular, the radical R, comprising 3 to 12 carbon atoms, of the substituted anionic compound is derived from a carboxylic diacid, an amino acid or a diol.

The AA radical is derived from an aromatic amino acid having a phenyl or a substituted or unsubstituted indole, or an aromatic amino acid derivative having a phenyl or a substituted or unsubstituted indole. In particular, the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.

[000383] The radical AA is linked to the radical E or the radical R by a function F or F "involving the amine of the aromatic amino acid or an aromatic amino acid derivative.

By "aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole" is meant a compound comprising from 7 to 20 carbon atoms, a substituted or unsubstituted phenyl or indole, an amino function and a functional group. acid.

FIRE I LLE OF REM PLACEM ENT (RULE 26) The term "aromatic amino acid derivative" is intended to mean the decarboxylated derivatives, the amino-alcohol derivatives, or amino-amides corresponding to the aromatic amino acids comprising a substituted or unsubstituted phenyl or indole. The derivatives of said aromatic amino acids comprising a substituted or unsubstituted phenyl or indole may in particular be chosen from amino-alcohols and amino-amides.

According to one embodiment AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids. Aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.

According to one embodiment, the aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole is a natural amino acid, especially chosen from phenylalanine, tyrosine and tryptophan, especially phenylalanine.

[000388] The aromatic amino acids comprising a phenyl or a substituted or unsubstituted indole, and their derivatives may, where appropriate, be in laevorotatory, dextrorotatory or racemic form. In particular they are in laevorotic form.

[000389] According to one embodiment, the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals.

In one embodiment, the radical E is derived from a linear or branched alkyl compound comprising at least two functions selected from the group consisting of -OH, -COOH, -NH ₂ .

In particular, the radical E is derived from a compound comprising from 2 to 6 carbon atoms, and optionally comprising 1 or 2 carboxylic acid functions and / or 1, 2 or 3 alcohol functions.

[000392] The radical E is an at least divalent radical, in particular divalent, trivalent or tetravalent radical.

The radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3. propanediol or TRIS, serinol, and threoninol. According to one embodiment, when the radical E is derived from an amino-diol or an amino-triol, it is respectively substituted with 2 or 3 AA radicals.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E does not comprise an -NH ₂ function.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the radical E is different from the radical R.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E is different from the precursor of the radical R.

According to one embodiment, the substituted anionic compound comprises from 2 to 8, in particular from 2 to 6, or even from 2 to 4 carboxylic acid functions.

[000401] In one embodiment, m + n <P = 1.

[000402] In one embodiment, m + n * P = 2.

[000403] In one embodiment, m + n * ^k P = 3.

[000404] In one embodiment, m + n * * p = 4.

[000405] In one embodiment, m + n ^has P = 5.

In one embodiment, m + n ⁵ P = 6.

In one embodiment, m + n "* p = 7.

[000408] In one embodiment, m + n '' P = 8.

The calculation m + n * p gives the number of carboxylate functions provided by AA. When the radical R, comprising 3 to 12 carbon atoms, comprises free carboxylate functions, then the total number of free carboxylate functions is greater than m + n * p.

In one embodiment, the substituted anionic compound does not comprise an AA radical linked via a spacer E, the substituted anionic compound can have the formula I in which n 0 and corresponds to formula II: Formula II

AA, F and R have the definitions given above,

In one embodiment, the substituted anionic compound is selected from the anionic compounds of formula II wherein m = 1:

AA

\ FR _Form VIII

- AA, F and R have the definitions given above,

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula II in which = 2:

AA, F and R have the definitions given above,

According to one embodiment, the substituted anionic compound does not comprise an AA radical bonded via the F function to the radical R. Thus, the substituted anionic compound may correspond to Formula I in which m = 0.

In one embodiment, the substituted anionic compound does not comprise an AA radical bonded via the F moiety to the R radical, the substituted anionic compound can meet the Form and corresponds to the formula III: Formula III

AA, E, F ', F ", p and R are as defined above,

[000416] In one embodiment, the substituted anionic compound is chosen from the anionic compounds in which n = 1: Formula X In one embodiment, the substituted anionic compound is chosen from the compounds n = 2:

Form XI

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula III, X or XI in which p = 1.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula III, X or XI in which p = 2.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula III, X or XI in which p = 3.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula III or X in which n = 1 and p = 3.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula III or XI in which n = 2 and p = 3

Formula I

in which :

R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 6 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions;

F, F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of a AA radical, F 'being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E, AA is a radical derived from an aromatic amino acid comprising a phenyl group or an indole group, substituted or unsubstituted, or an aromatic amino acid derivative having a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function, E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms,

p being an integer from 1 to 3,

said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na ^* and K ⁺ .

In one embodiment, if m + n * p = 1, then R comprises at least one carboxylic acid function. * represents the mathematical sign multiplication.

In one embodiment, the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the R, AA or E radicals.

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radicals R and E.

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the AA and E radicals.

In one embodiment, the at least two carboxylic acid functional groups in the form of an alkali metal salt are carried by the AA radical.

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radical E.

In one embodiment, F is chosen from amide or carbamate functions.

[000433] In one embodiment, F is an amide function.

[000434] In one embodiment, F is a carbamate function.

[000435] In one embodiment, F 'is a urea function.

[000436] In one embodiment F 'is an amide function.

[000437] In one embodiment, F 'is a carbamate function.

In one embodiment, F and F 'are chosen from amide or carbamate functions.

[000439] In one embodiment, F and F 'are amide functions.

[000440] In one embodiment, F and F 'are carbamate functions.

[000441] In one embodiment, F "is a urea function. [000442] In one embodiment F "is an amide function.

[000443] In one embodiment, F "is a carbamate function.

[000444] In one embodiment, F 'is an amide function and F "is a carbamate function.

The radical R, comprising 3 to 12 carbon atoms, may be a linear, branched or cyclic hydrocarbon radical, and may be saturated or unsaturated.

In particular, the radical R, comprising 3 to 12 carbon atoms, is a saturated linear hydrocarbon radical.

[000447] In one embodiment, m + n = 6.

[000448] In one embodiment, m + n = 5.

[000449] In one embodiment, m + n = 4.

[000450] In one embodiment, m + n = 3.

[000451] In one embodiment, m + n = 2.

[000452] In one embodiment, m + n = 1.

In one embodiment, the substituted anionic compound, when bisubstituted, is chosen from the compounds of formula I in which the radical -R- is chosen from carbon radicals of formula IV:

Form IV

6 <r * t + q <12, a is 0 or 1, when _q R i, R _q2, R _r and R i _r2 are independently of each other, selected from -H, -OH or -COOH; 5 <q + r * t <12, a is 0 or 1, where the groups R _ql, _q2 R, R _r and R i _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

4 <r * t + q <12, a is 0 or 1, where the groups R _ql, _q2 R, R _r and R _r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R _q or R _{r groups} are -COOH.

If a = 0 then t = 0. When q> 1 and / or t> 1, then R _q1 and R _q2 and R _r i and R _r2 are the same or different from one carbon to another.

[000454] In one embodiment, a is equal to 1. In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from compounds of formula I in which the radical -R-, comprising 6 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms,

Form IV

6 <r * t + q <12, a is 0 or 1, when _q R i, R _q2, R _r and R i _r2 are independently of each other, selected from -H, -OH or -COOH; 5 <q + r * t <12, a is 0 or 1, where the R groups _ql> R _q2, R _r and R i _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

4 <r * t + q <12, a is 0 or 1, where the groups R _{ql /} _q2 R, R _r and R _r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R _q or R _{r groups} are -COOH.

If a = 0 then t = 0. When q≥ 1 and / or t> 1, then the R _ql and R _q2 and the R _rl and R _r2 are identical or different from one carbon to another.

[000456] In one embodiment, a is equal to 1.

In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 6 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV ":

in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and: 5 <q + r * t <11, a is 0 or 1 when the groups R _q1; R _q2 , R _r and R _r2 are, independently of each other, selected from -H, -OH, -COOH; 4 ≤ q + r * t <11, a is 0 or 1, where the groups R _qi, _q2 R, R _r and R i _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

If a = 0 then t = 0. When q> 1 and / or t> 1, then the R _q i and R _q2 and the R _rl and R _r2 are identical or different from one carbon to another.

[000458] In one embodiment, a is equal to 1.

In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from compounds of formula I in which the radical -R- comprising 6 to 12 carbon atoms is chosen from radicals comprising 3. to 12 carbon atoms of formula IV ":

Formula IV "in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and:

6 <r * t + q <12, a is 0 or 1, when _q R i, R _q2, _rl R and R _r2 are independently of each other, selected from -H, -OH or - COOH; 5 <q + r * t <12, a is 0 or 1, where the groups R _ql, _q2 R, R _r and R i _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

4 <r * t + q <12, a is 0 or 1, when _q R i, R _q2, R _r and R _r2 are independently of each other, selected from -H, -OH, or -COOH and at least two groups R _q or R _r are -COOH.

[000460] In one embodiment, a is equal to 1.

In one embodiment, the -R- radical,

In one embodiment, the -R- radical, when bisubstituted, is chosen from radicals comprising 6 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , represented by the formula V:

in which :

- q is an integer between 6 and 12, when the groups R _q i and R _q2 are, independently of each other, selected from -H, -OH and -COOH;

- q is an integer between 5 and 12, when the R i groups and R _q _q2 are independently from each other selected from -H, -OH and -COOH and at least one Rq is -COOH.

- q is an integer between 4 and 12, when the R _qi and _q2 R groups are independently from each other selected from -H, -OH and -COOH, and at least two R _q are -COOH.

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals comprising 6 to 12 carbon atoms, of formula IV in

V:

in which :

- q is an integer between 6 and 12, when the R _qi and _q2 R groups are independently from each other selected from -H, -OH;

q is an integer between 5 and 12, when the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH and -COOH and at least one Rq is a -COOH.

q is an integer between 4 and 12, when the groups R _q i and R _q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R _q are -COOH .

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals comprising 6 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , represented by the formula V ": Formula V "

in which :

- q is an integer between 5 and 11, when the groups R i and R _q2 _q are, independently from each other selected from -H, -OH;

q is an integer between 4 and 11, when the groups R _q i and R _q2 are, independently of one another, chosen from -H, -OH and -COOH and at least one R _q is a -COOH .

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals, comprising 6 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0, V ":

in which :

q is an integer between 6 and 12, when the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH;

- q is an integer between 5 and 12, when the groups R and R _qI _q2 are independently from each other selected from -H, -OH and -COOH and at least one R _q is -COOH.

- q is an integer between 4 and 12, when the R _ql and _q2 R groups are independently from each other selected from -H, -OH and -COOH, and at least two R _q are -COOH.

In one embodiment, when the substituents are linked by a function derived from an acid function of the precursor of R, the substituted anionic compound is chosen from the compounds of formula I in which the radical -R- is a radical. derived from a compound comprising 6 to 12 + (m + n) carbon atoms.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 6 and the radical -R- is a radical derived from a compound comprising 6 to 18 carbon atoms. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 4 and the radical -R- is a radical derived from a compound comprising 6 to 16 carbon atoms.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 2 and the radical -R-, comprising 6 to 12 carbon atoms, is a radical derived from a compound having 6 to 14 carbon atoms of formula VI:

Form VI

Wherein q and r are integers between 0 and 12, groups R _ql, _q2 R, R and R _rl _r2 are independently of each other, selected from -H, -OH, -COOH,

-X and -Y are the same or different reactive functions which react with the precursor of E or AA to form respectively F 'or F, and are chosen from -COOH, -OH, -NH ₂ ,

- a is 0 or 1, and

- 3 <q + r * t <12, when all X, Y, R _q1, R _q2 , R _r1 and R _r2 are different from - COOH,

- 2 <q + r * t <11, when at least one of X, Y, R _q, R _q2, R _rl and _r2 R is -COOH, and if it is X or Y then n ' is not involved in a function F or F ',

-1 <q + r * t <11, where at least two of X, Y, R _q, R _q2, R _rl and _r2 R is -COOH, and if it is X or Y when it is not not involved in an F or F 'function,

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 1 and the radical -R- is a radical derived from a compound comprising 6 to 13 carbon atoms, of formula VI above and if-X or -Y is -NH ₂ then it is the group that reacts with the precursor of E or AA to form F 'or F.

In one embodiment, the radical -R-, comprising 6 to 12 carbon atoms, is a radical derived from a compound of formula VI, in which t = 0, a = 0 and r = 0, represented by the formula VII: Form VII

In which, the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH, -COOH,

-X and -Y are the same or different reactive functions that react with the precursor of E or AA to form F 'or F, respectively, and are selected from -COOH, -OH, -NH ₂ ,

- 3 <q <12, when all X, Y, R _q1, R _q2 are different from -COOH,

- 2 <q <11, when at least one of X, Y, R _qi, R _q2 is -COOH, and if it is X or Y then it is not involved in a function F or F ' ,

-1 <q <11, when at least two of X, Y, R _q i, R _q2 is -COOH, and if it is X or Y then it is not involved in a function F or F ' ,

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 1 and the radical -R- is a radical derived from a compound comprising 6 to 13 carbon atoms, of formula VI above and if -X or -Y is -NH ₂ then it is the group that reacts with the precursor of E or AA to form F 'or F.

In one embodiment, the precursor of R is chosen from the precursor of formula VI or VII in which -X and -Y, identical or different, are chosen from -COOH, -OH.

The radical R, comprising 6 to 12 carbon atoms, may comprise at least one function, in particular chosen from the alcohol and carboxylic acid functions.

According to another embodiment, the radical R, comprising 6 to 12 carbon atoms, is free of carboxylic acid functions.

According to one embodiment, the radical R, comprising 6 to 12 carbon atoms, comprises at least one alcohol function, in particular it comprises 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions. According to another embodiment, the radical R, comprising 6 to 12 carbon atoms, is devoid of alcohol function.

According to one embodiment, the radical R, comprising 6 to 12 carbon atoms, comprises 1 or 2 alcohol functions and 1 carboxylic acid function.

The radical R, comprising 6 to 12 carbon atoms, may come from a polycarboxylic acid, especially a dicarboxylic acid.

According to one embodiment, all the carboxylic acid functions of the polycarboxylic acid are involved in the functions F and F '.

[000482] Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are involved in the functions F and F '.

According to another embodiment, all the acid functional groups of the polycarboxylic acid are not involved in the functions F and F '.

[000484] Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are not involved in the F and F 'functions.

The radical R, comprising 6 to 12 carbon atoms, may be derived from a dicarboxylic acid selected from heptanedioic acid, octanedioic acid, nonanedioic acid.

The radical R, comprising 6 to 12 carbon atoms, may be derived from a diol. The diol may be chosen from triethylene glycol and tetraethylene glycol, hexanediol, heptane diol and octane diol.

In particular, the radical R, comprising 6 to 12 carbon atoms, of the substituted anionic compound is derived from a dicarboxylic acid, an amino acid or a diol.

The AA radical is derived from an aromatic amino acid having a phenyl or a substituted or unsubstituted indole, or an aromatic amino acid derivative having a phenyl or an indole, substituted or unsubstituted. In particular, the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.

The AA radical is bonded to the radical E or to the radical R by a function F or F 1 involving the amine of the aromatic amino acid or an aromatic amino acid derivative. By "aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole" is meant a compound comprising from 7 to 20 carbon atoms, a substituted or unsubstituted phenyl or indole, an amino function and a functional group. acid.

The term "aromatic amino acid derivative" is intended to mean the decarboxylated derivatives, the amino-alcohol derivatives, or amino-amides corresponding to the aromatic amino acids comprising a substituted or unsubstituted phenyl or indole. The derivatives of said aromatic amino acids comprising a substituted or unsubstituted phenyl or indole may in particular be chosen from amino-alcohols and amino-amides.

[000493] According to one embodiment AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids. Aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.

[000495] The aromatic amino acids comprising a phenyl or an indole, substituted or not, and their derivatives may, where appropriate, be levorotatory, dextrorotatory or in racemic form. In particular they are in laevorotic form.

According to one embodiment, the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals.

In one embodiment, the radical E is derived from a linear or branched alkyl compound comprising at least two functions chosen from the group consisting of -OH, -COOH, -NH ₂ .

[000499] The radical E is an at least divalent radical, in particular divalent, trivalent or tetravalent radical.

According to one embodiment, the radical E is derived from a linear or branched alkyl compound, optionally carrying one or two carboxylic acid functions. The radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3 propanediol or TRIS, serinol, and threoninol.

According to one embodiment when the radical E is derived from an amino-diol or an amino-triol, it is respectively substituted with 2 or 3 AA radicals.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the precursor of radical E is different from the precursor of radical R. According to one embodiment, the substituted anionic compound comprises from 2 to 8, in particular from 2 to 6, or even from 2 to 4 carboxylic acid functions.

[000508] In one embodiment, m + n *> P = 1.

[000509] In one embodiment, m + n * * P = 2.

[000510] In one embodiment, m + n * ^f P = 3.

[000511] In one embodiment, m + n ^s p = 4.

[000512] In one embodiment, m + n '* p = 5.

[000513] In one embodiment, m + n ^> 'P = 6.

[000514] In one embodiment, m + n * * P = 7.

[000515] In one embodiment, m + n '* P = 8.

The calculation m + n * p gives the number of carboxylate functions provided by AA.

When the radical R, comprising 6 to 12 carbon atoms, comprises free carboxylate functions, then the total number of free carboxylate functions is greater than m + n * p.

According to one embodiment, the substituted anionic compound does not comprise an AA radical bonded via a spacer E. Thus, the substituted anionic compound can correspond to Formula I in which n = 0. In one embodiment, the substituted anionic compound does not comprise an AA radical linked via a spacer E, the substituted anionic compound can correspond to formula I in which n formula II:

- AA, F and R have the definitions given above,

- 1 <m <6.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula II in which m = 1:

AA

\ ^F R Form VIII

AA, F and R have the definitions given above,

In one embodiment, the substituted anionic compound does not comprise an AA radical bonded via the F function to the R radical, the substituted anionic compound can meet the Form and corresponds to the formula III: Formula III

- AA, E, F, F ", p and R have the definitions given above,

- 1 <n <6.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula III in which n = 1:

p Formula X

AA, E, F ', F ", p and R are as defined above,

[000525] In one embodiment, the substituted anionic compound is chosen from among comp n = 2:

Form XI

AA, E, F ', F ", p and R are as defined above,

- 1 <p <3.

Form XII

in which :

R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 3 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions, F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F" being a function resulting from a reaction involving the amine of the aromatic amino acid, precursor of the radical AA, F being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E,

AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function, - E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms,

p being an integer from 1 to 3,

n is an integer from 1 to 6;

said compound comprising at least 2 carboxylic acid functional groups in the form of an alkali metal salt selected from Ma ⁺ and K ⁺ .

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the R, AA or E radicals.

In one embodiment, the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radicals R and E.

In one embodiment, the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the radicals R and AA.

In one embodiment, if n * p = 1, then R comprises at least one carboxylic acid function. * represents the mathematical sign multiplication.

[000540] In one embodiment, F 'is a urea function.

[000541] In one embodiment F 'is an amide function.

[000542] In one embodiment, F 'is a carbamate function. [000543] In one embodiment, F "is a urea function.

[000544] In one embodiment F "is an amide function.

[000545] In one embodiment, F "is a carbamate function.

[000546] In one embodiment, F 'is an amide function and F "is a carbamate function.

[000547] In one embodiment, the radical R may comprise from 4 to 10 carbon atoms, in particular from 4 to 6 carbon atoms.

[000549] In one embodiment, n = 6.

[000550] In one embodiment, n = 5.

[000551] In one embodiment, n = 4.

[000552] In one embodiment, n = 3.

[000553] In one embodiment, n = 2.

[000554] In one embodiment, n = 1.

Form IV

3 ≤ q + r * t <12, a is equal to 0 or 1, when the groups R _{q1 (} R _q2 , R _r i and R _r2 are, independently of one another, chosen from -H, -OH or - COOH; 2 <q + r * t <12, a is 0 or 1, where the groups R _qli R _q2, R _r and R _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

1 <q + r * t <12, a is 0 or 1, when the groups R _q1 , R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH, or -COOH and at least two groups R _q or R _r are -COOH.

If a = 0 then t = 0. When q≥ 1 and / or t> 1, then the R _ql and R _q2 and the R _rl and R _r2 are identical or different from one carbon to another. In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms,

3 <r * q + t ≤ 12, a is 0 or 1, when _q R i, R _q2, _rl R and R _r2 are independently of each other, selected from -H, -OH or - COOH;

2 <q + r * t <12, a is 0 or 1, when the groups R _q1 , R _q2 , _r i and R _r2 are, independently of one another, selected from -H, -OH, or - COOH and at least one R _q or R _r is -COOH.

1 <q + r * t <12, a is 0 or 1, where the groups R _ql, _q2 R, R and R _rl _r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R _q or R _{r groups} are -COOH.

In one embodiment, the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV ":

Formula IV "in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and: 2 q q + r * t 11 11, a is equal to 0 or 1, when the groups R _q1, R _q2 , R _r and R _r2 are, independently of one another, chosen from -H, -OH, - COOH; 1 <q + r * t <11, a is equal to 0 or 1, when the groups R _{qi <} R _q2 , R _r i and R _r2 are, independently of one another, chosen from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

3 <r * t + q <12, a is 0 or 1 when R _ql, _q2 R, R and R _rl _r2 are independently of each other, selected from -H, -OH or -COOH ; 2 <q + r * t <12, a is 0 or 1, when _q R i, R _q2, _rl R and R _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

1 <q + r * T≤ 12, a is 0 or 1, when _q R groups _(R _q2, _rl R and R _r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R _q or R _{r groups} are -COOH.

If a = 0 then t = 0. When q> 1 and / or t≥ 1, then R _gl and R _q2 and R _rl and R _r2 are identical or different from one carbon to another.

In one embodiment, the -R- radical,

In one embodiment, the -R- radical, when bisubstituted, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , represented by the formula V:

in which :

- q is an integer between 3 and 12, when the R _qi and _q2 R groups are independently from each other selected from -H, -OH, and -COOH;

q is an integer between 2 and 12, when the groups R _q1 and R _q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one Rq is a -COOH.

- q is an integer between 1 and 12, when the groups R i and R _q2 _q are, independently from each other selected from -H, -OH and -COOH, and at least two R _q are -COOH .

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , r V:

in which :

q is an integer between 3 and 12, when the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH and -COOH;

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0 , represented by the formula V ": Formula

in which :

- q is an integer between 2 and 11, where R _q, and R _q2 groups are independently from each other selected from -H, -OH and -COOH;

- q is an integer between 1 and 11, when the groups R _qi and R _q2 are, independently of each other, selected from -H, -OH and -COOH and at least one R _q is a -COOH.

In one embodiment, the -R- radical, when monosubstituted, is chosen from radicals, comprising 3 to 12 carbon atoms, of formula IV in which t = 0, a = 0 and r = 0, r the formula V ":

Formula V

in which :

q is an integer between 2 and 12, when the groups R _q1 and R _q2 are, independently of one another, chosen from -H, -OH and -COOH and at least one R _q is a -COOH.

q is an integer between 1 and 12, when the groups R _q) and R _q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R _q are -COOH .

In one embodiment, the substituted anionic compound is chosen from compounds of formula I in which the radical -R- is a radical derived from a compound comprising 3 to 12 + n carbon atoms.

In one embodiment, the substituted anionic compound is chosen from compounds of formula I in which n = 6 and the radical -R- is a radical derived from a compound comprising 3 to 18 carbon atoms. In one embodiment, the substituted anionic compound is chosen from compounds of formula I in which n = 4 and the radical -R- is a radical derived from a compound comprising 3 to 16 carbon atoms.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which m + n = 2 and the radical -R-, comprising 3 to 12 carbon atoms, is a radical derived from a compound having 3 to 14 carbon atoms of formula VI:

Form VI

Wherein q and r are integers between 0 and 12, groups R _qi, _q2 R, R _r and R i _r2 are independently of each other, selected from -H, -OH, -COOH,

- a is 0 or 1, and

- 3 <q + r * t <12, when all of X, Y, R _{q lj} R _q2, R _r and R _r2 are different from - COOH,

- 2 <q + r * t <11, when at least one of X, Y, R _q i, R _q2 , R _rl and R _r2 is -COOH, and if it is X or Y then it n 'is not involved in a function F or F',

-1 <q + r * t <11, when at least two of X, Y, R _q i, R _q2 , R _r1 and R _r2 is -COOH, and if it is X or Y then it is not is not involved in a function F or F ',

In one embodiment, the radical -R-, comprising 3 to 12 carbon atoms, is a radical derived from a compound of formula VI, in which t = 0, a = 0 and r = 0, represented by the form

Form VII

In which, the R _q1 and R _{q2 groups} are, independently of one another, chosen from -H, -OH, -COOH, -X and -Y are the same or different reactive functions which react with the precursor of E or AA to form respectively F 'or F, and are chosen from -COOH, -OH, -NH ₂ ,

- 3 <q <12, when all X, Y, R _q1 , R _q2 are different from -COOH,

-1 <q <11, when at least two of the X, Y, R _q! , R _q2 is -COOH, and if it is X or Y then it is not involved in a function F or F ', [000569] In one embodiment, the substituted anionic compound is selected from the compounds of formula I in which n = 1 and the radical -R- is a radical derived from a compound comprising 3 to 13 carbon atoms, of formula VI above and if -X or -Y is -NH ₂ then it s is the group that reacts with the precursor of E to form F '.

[000570] In one embodiment, the precursor of R is chosen from the precursor of formula VI or VII in which -X and -Y, which are identical or different, are chosen from -COOH, -OH. [000571] The radical R, comprising 3 to 12 carbon atoms, may comprise at least one function, in particular chosen from the alcohol and carboxylic acid functions.

[000573] According to another embodiment, the radical R, comprising 3 to 12 carbon atoms, is free of carboxylic acid functions.

According to one embodiment, the radical R, comprising 3 to 12 carbon atoms, comprises at least one alcohol function, in particular it comprises 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions.

[000575] According to another embodiment, the radical R, comprising 3 to 12 carbon atoms, is devoid of alcohol function.

[000576] According to one embodiment, the radical R, comprising 3 to 12 carbon atoms, comprises 1 or 2 alcohol functions and 1 carboxylic acid function.

The radical R, comprising 3 to 12 carbon atoms, can come from a polycarboxylic acid, especially a dicarboxylic acid.

According to one embodiment, all the carboxylic acid functions of the polybasic carboxylic acid are involved in the functions F '. [000579] Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are involved in the functions F '.

According to another embodiment, all the acid functions of the polycarboxylic acid are not involved in the functions F '.

[000581] Thus, according to this embodiment, all the carboxylic acid functions of the precursor of R are not involved in the F functions.

In particular, 1 or 2 carboxylic acid functions are not involved in the functions F ', especially 1 carboxylic acid function is not involved in the functions F'.

The radical R, comprising 3 to 12 carbon atoms, may be derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, hexanedioic acid ( or adipic acid), heptanedioic acid, octanedioic acid, nonanedioic acid, pentanedioic acid, butenedioic acid, pentenedioic acid, and hexadienedioic acid (or adipic acid).

Even more particularly, the radical R, comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), malic acid or tartaric acid.

[000587] The radical R, comprising 3 to 12 carbon atoms, may be derived from an amino acid.

The radical R, comprising 3 to 12 carbon atoms, may be derived from a diol. The diol may be chosen from diethylene glycol, triethylene glycol and tetraethylene glycol, propane diol, butanediol, pentanediol, hexanediol, heptane diol and octane diol. In particular, the radical R, comprising 3 to 12 carbon atoms, of the substituted anionic compound is derived from a dicarboxylic acid, an amino acid or a diol. The AA radical is derived from an aromatic amino acid having a phenyl or a substituted or unsubstituted indole, or an aromatic amino acid derivative having a phenyl or an indole, substituted or unsubstituted. In particular, the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.

The AA radical is linked to the radical E by a function F "involving the amine of the aromatic amino acid or an aromatic amino acid derivative.

[000595] According to one embodiment AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids. Aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.

[000597] The aromatic amino acids comprising a phenyl or an indole, substituted or not, and their derivatives may, where appropriate, be levorotatory, dextrorotatory or in racemic form. In particular they are in laevorotic form.

[000598] According to one embodiment, the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals. In one embodiment, the radical E is derived from a linear or branched alkyl compound comprising at least two functions selected from the group consisting of -OH, -COOH, -NH ₂ .

[000601] The radical E is an at least divalent radical, in particular divalent, trivalent or tetravalent radical.

The radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3 propanediol or TRIS, serinol, and threoninol.

In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the precursor of radical E is different from the precursor of radical R. According to one embodiment, the substituted anionic compound comprises of

2 to 8, in particular from 2 to 6, or even from 2 to 4 carboxylic acid functions.

[000610] In one embodiment, n * p = 1.

[000611] In one embodiment, n * p = 2.

[000612] In one embodiment, n * p = 3.

[000613] In one embodiment, n * p = 4.

[000614] In one embodiment, n * p = 5.

[000615] In one embodiment, n * p = 6.

[000616] In one embodiment, n * p = 7. [000617] In one embodiment, n * p = 8.

[000618] The calculation n * p gives the number of carboxylate functions provided by AA. When the radical, comprising 3 to 12 carbon atoms, comprises free carboxylate functions, then the total number of free carboxylate functions is greater than n * p.

In one embodiment, the substituted anionic compound is chosen from the anioni compounds in which n = 1:

p Formula X

- AA, E, F ', F ", p and R have the definitions given above,

[000620] In one embodiment, the substituted anionic compound is chosen from the compounds n = 2:

Formula XI - AA, E, F ', F ", p and R are as defined above,

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula XII, X or XI in which p = 1.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula XII, X or XI in which p = 2.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula XII, X or XI in which p = 3.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula XII or X in which n = 1 and p = 3.

In one embodiment, the substituted anionic compound is chosen from the anionic compounds of formula XII or XI in which n = 2 and p = 3 Examples

Table 1 below shows, without limitation, examples of compounds according to the invention.

Part A: Synthesis of substituted anionic compounds

Example A1: Substituted anionic compound Al

The substituted anionic compound Al or N- (3-carboxy-1-oxopropyl) -L-phenylalanine is obtained according to a modification of the process described in the application WO 96/33699 (Milstein, S.) starting from l ethyl ester of L-phenylalanine and

Ο, Ο'-diacetyl-tartaric anhydride.

[000628] Yield: 6.7 g (26%)

[000629] 1 H NMR (D SO d ₆ ppm): 3.10 (2H); 4.20 (1H); 4.30 (1H); 4.50 (1H); 7.25 (5H); 7.70 (1H).

Example A2: Substituted anionic compound A2

Molecule 1: isocyanate of L-phenylalanine ethyl ester

[000630] To a solution of L-phenylalanine ethyl ester hydrochloride salt (23 g, 100 mmol) in a mixture of dichloromethane (400 mL) and a saturated aqueous sodium hydrogencarbonate solution (400 mL) at 0 ° C is added in one portion of the triphosgene (9.8 g, 33 mmol). After stirring for 1 h at 0 ° C., the organic phase is separated and the aqueous phase extracted 3 times with dichloromethane. The combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated to give a colorless oil which crystallizes progressively.

[000631] Yield: 22 g (quantitative)

[000632] NMR ^J H (CDCl _3, ppm): 1.24 (3H); 2.98 (1H); 3.11 (1H); 4.17-4.23 (3H); 7.14-7.28 (5H).

Molecule 2: product obtained by reaction between tris (hydroxymethyl) aminomethane and mono-methylsuccinate

[000633] By a method similar to that described in J. Org. Chem. 2011, 76, 2084 by reaction between tris (hydroxymethyl) aminomethane (2.66 g, 22 mmol) and mono-methylsuccinate (2.64 g, 20 mmol), a white solid is obtained.

[000634] Yield: 3.77 g (80%)

[000635] ^X H NMR (CDCl _3, ppm): 2.52 (2H); 2.71 (2H); 3.64-3.70 (9H); 6.69 (1H). Molecule 3: product obtained by reaction between molecule 2 and molecule 1

Under nitrogen to a solution of molecule 2 (1.68 g, 7.14 mmol) and molecule 1 (5.63 g, 25.7 mmol) in toluene (70 mL) is added 1.4 diazabicyclo [2.2.2] octane (DABCO) (136 mg, 1.21 mmol) and the mixture is heated at 90 ° C for 2.5 days. After concentration of the reaction medium under vacuum and co-evaporation of toluene with ethanol, the residue obtained is taken up in dichloromethane and washed with 1N HCl. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography (Cyclohexane / ethyl acetate) gives the desired product as a colorless oil.

[000637] Yield: 5.15 g (80%)

[000638] RNH (CDCl ₃ , ppm): 1.24 (9H); 2.39 (2H); 2.59 (2H); 2.90-3.15 (6H); 3.63 (3H); 4.10-4.30 (9H); 4.45-4.60 (6H); 6.07 (3H); 7.10-7.35 (15H).

Substituted anionic compound A2

Under nitrogen, a suspension of molecule 3 (10.2 g, 11.43 mmol) in an ethanol / tetrahydrofuran (THF) / water mixture (50 mL / 32 mL / 32 mL) is treated with 2N NaOH (23.4 g). , 4 mL) and then stirred at room temperature overnight. The volatile solvents are evaporated under vacuum and then 25 ml of 2N HCl are gradually added to the medium. The medium is then extracted with ethyl acetate and the organic phase is dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a foam. After trituration in pentane and ethyl ether, filtration and drying under vacuum, a whitish solid corresponding to the anionic molecule A2 in acid form is obtained. The solid is dissolved in a mixture of water / 1-butanol (50/50 vol.) And freeze-dried.

[000640] Yield: 5.9 g (86%)

1H NMR (DMSO-d ₆ , ppm): 2.10-2.20 (4H); 2.80-3.10 (6H); 4.00 - 4.20 (9H); 7.10-7.30 (15H); 7.50-7.60 (4H); 12.20-12.80 (4H).

[000642] LC / MS (ESI): 795.3; (calculated ([M + H] ⁺ ): 795.3).

The substituted anionic compound A2 in acid form is dissolved in water and the solution is neutralized by gradual addition of 10N sodium hydroxide to give an aqueous solution of substituted anionic compound A2 which is then lyophilized.

[1 H NMR (D ₂ O, ppm): 2.25-2.40 (4H); 2.75 - 2.90 (3H); 3.10-3.30 (3H); 3.75-4.30 (9H); 7.10-7.40 (15H).

Example A5: anionic compound substituted A5

To a solution of L-phenylalanine (25 g, 0.15 mol) in THF (200 mL) at room temperature is added triethylamine (30.6 g, 0.3 mol) and then a solution of succinic anhydride (15.1 g, 0.15 mol) in THF (189 mL). The reaction medium is boiled and heated for 16 hours. After returning to ambient temperature, the medium is concentrated in vacuo at ¾ and acidified to pH 1.5 by addition of 12N HCl. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with 1N HCl and concentrated in vacuo to give a yellow viscous oil. This oil is taken up in water and the solution is stirred at pH 12 for 3 h following the addition of ION sodium hydroxide. The solution is then neutralized and then acidified by addition of 12N HCl to pH 1.5. The solution is extracted with ethyl acetate, concentrated in vacuo and dried under vacuum to give a white solid of substituted anionic compound A5 in acid form.

[000646] Yield: 26.9 g (67%)

[000647] 1 H NMR (DMSO-d6, ppm): 2.33 (4H); 2.75-3.15 (2H); 4.42 (1H); 7.21 (5H); 8.18 (1H); 12.38 (2H).

[000648] LC / MS (ESI): 266.2; (calculated ([M + H +]): 266.3).

The substituted anionic compound A5 in acid form is dissolved in water and the solution is neutralized by progressive addition of ION sodium hydroxide to give an aqueous solution of substituted anionic compound A5 or N- (-carboxypropionyl) -L-phenylalanine which is then lyophilized.

[H NMR (D ₂ O, ppm): 2.25-2.45 (4H); 2.65-2.92 (1H); 3.08-3.19 (1H); 4.35-4.45 (1H); 7.05-7.39 (5H)

Example A6: substituted anionic compound A6

Molecule 9: / V- [2-Hydroxy-1,1-bis (hydroxymethyl) ethyl] -1,1-dimethylethyl ester of carbamic acid

The molecule 9 is obtained according to the method described in patent WO2008 / 30119 starting from 20 g of tris (hydroxymethyl) aminomethane.

[000652] Yield: 33.2 g (88%)

[H NMR (DMSO-d ₆ , ppm): 1.37 (9H); 3.50 (6H); 4.48 (3H); 5.76 (1H). Molecule 10: product obtained by reaction between molecule 1 and molecule 9

To a solution of molecule 9 (4 g, 18.08 mmol) and of molecule 1 (11.87 g, 57.9 mmol) in toluene (260 mL) under argon is added 1,4-diazabicyclo [2.2.2] octane (DABCO) (795 μl, 7.2 mmol) and the mixture is heated at 110 ° C for 3 h and then at 90 ° C overnight. After concentration in vacuo, the medium is taken up in ethyl acetate and then washed with 1N HCl. The organic phase is washed with a saturated solution of NaCl, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is purified by flash chromatography (cyclohexane / ethyl acetate).

[000655] Yield: 7.5 g (50%)

NMR ^: H (CDCl ₃ , ppm): 1.41 (9H); 2.85-3.20 (6H); 3.73 (9H); 4.25 (3H); 4.39 (3H); 4.57 (3H); 5.72 (3H); 7, 10-7.35 (15H).

[000657] LC / MS (ESI): 837.7; (calculated ([M + H ⁺ ]): 837.8).

Molecule 11: Hydrochloride salt of the product obtained by deprotection of the Boc group of the molecule 10

Under argon, a solution of the molecule (7.5 g, 9 mmol) in dichloromethane at 0 ° C. is treated with a solution of 4N HCl in dioxane (22.4 ml). The medium is stirred at 0 ° C. at ambient temperature for 3 hours and then is concentrated in vacuo to give a white gum which is dried under vacuum at room temperature for 15 h.

[000659] Yield: 6.84 g (99%)

NMR ^: H (CDCl ₃ , ppm): 3.02-3.20 (6H); 3.73 (9H); 4.19 (3H); 4.42 (3H); 4.55 (3H); 5.72 (3H); 7.15-7.35 (15H); 8.93 (3H).

LC / MS (ESI): 737.4; (calculated ([M-Cl]): 737.7).

Molecule 12: product obtained by reaction between molecule 11 and Ο, Ο'-diacetyl-tartaric anhydride

The molecule 11 (5.7 g, 7.4 mmol) is solubilized in dichloromethane (50 mL) and a saturated solution of NaHCO ₃ (30 mL) is added. The aqueous phase is extracted with dichloromethane and the organic phase is dried over Na ₂ SO ₄ , filtered and concentrated to a volume of approximately 20 ml. This solution is poured onto a solution of Ο, Ο'-diacetyl tartaric anhydride (1.6 g, 7.4 mmol) in THF (35 mL) at 0 ° C. After stirring for 4 h, the medium is concentrated in vacuo to give a white foam. The product is purified by flash chromatography (dichloromethane / methanol) to give a white foam.

[000661] Yield: 5.5 g (78%)

[000662] ^X H NMR (CDCl _3, ppm): 2.05 (3H); 2.15 (3H); 2.93 (3H); 3.05 (3H); 3.73 (9H); 4.19 (3H); 4.50 (6H); 5.60 (1H); 5.69 (1H); 6.30 (3H); 7.15-7.35 (15H); 7.92 (1H).

[000663] LC / MS (ESI): 953.6; (calculated ([M + H +]) 953.9).

Substituted anionic compound A6

To a solution of molecule 12 (5, 14 g, 5.39 mmol) in a methanol / water / THF mixture (18 mL / 18 mL / 18 mL) at 0 ° C. is added an aqueous 2N sodium hydroxide solution. (13.5 mL) and the mixture is stirred at 0 for 2 h. After removing the methanol and THF by evaporation under vacuum and washing the solution with ethyl acetate, the solution is cooled to 0 ° C and acidified to pH 1 by addition of a 10% aqueous solution of HCl. The precipitated product is extracted with ethyl acetate (3 x 100 mL). The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo to give a white solid. The residue is taken up twice in a methanol / toluene mixture and then evaporated to dryness in vacuo. The solid is suspended in water and the mixture is lyophilized.

[000665] Yield: 3.8 g (85%)

[000666] LC / MS (ESI): 827.4; (calculated ([M + H +]): 827.7).

The substituted anionic compound A6 (3.8 g) in acid form is suspended in water and 1.0025M sodium hydroxide is gradually added to pH 7.18. After lyophilization, the desired product is obtained as a white solid.

[000668] Yield: 4.09 g (83%) [000669] RN 1H (D ₂ O, 80 ° C, ppm): 3.45 (3H); 3.75 (3H); 4.55-4.75 (6H); 4.75-485 (4H); 5.00 (1H); 7.75-8.00 (15H).

[000670] LC / MS (ESI): 827.5; (calculated ([M + 3H + -3Na +]): 827.7). Example A7: A7 Substituted Anionic Compound

Molecule 13: product obtained by reaction between the molecule 5 and Ο, Ο'-diacetyl-tartaric anhydride

An aqueous solution (60 mL) of the molecule (4.99 g, 9.6 mmol) is poured into a saturated solution of NaHCO ₃ (60 mL) and the mixture is extracted with dichloromethane (3 x 30 mL) ). The organic phase is dried over Na ₂ SO, filtered and concentrated in vacuo to 2/3. It is added to a solution of Ο, Ο'-diacetyl tartaric anhydride (2.07 g, 9.6 mmol) in THF at 0 ° C and the mixture is stirred at 0 ° C for 30 min. The mixture is concentrated under vacuum to obtain a white foam.

Yield: 6.45 g (96%)

1H NMR (DMSO-d6, ppm): 1.01-1.10 (6H); 2.00 (3H); 2.10 (3H); 2.43 (4H); 2.80 - 2.95 (4H); 3.60 (1H); 3.95-4.05 (4H); 4.39 (2H); 4.60 (1H); 5.50 (2H); 7.19-7.30 (10H); 8.25-8.40 (3H); 13.50 (1H).

[000674] LC / MS (ESI): 700.3; (calculated ([M + H +]): 700.7).

Substituted anionic compound A7

To a solution of molecule 13 (5.39 g, 7.70 mmol) in a mixture of methanol / water (38 ml / 38 ml) at 0 ° C., an aqueous solution of 2N sodium hydroxide (15.4 ml) is added. ) and the mixture is stirred at 0 ° C for 1 h. Methanol is removed under reduced pressure and the volume of water is reduced to about 1/3. The medium is acidified at 0 ° C. by slow addition of a 10% aqueous solution of HCl and then extracted with ethyl acetate (3 × 50 ml). The organic phases are dried over Na ₂ SO ₄ , evaporated under reduced pressure to give a white solid of the substituted anionic compound A7 in acid form which is azeotroped 3 times with 50 ml of water to remove the traces of ethyl acetate and of acetic acid.

[000676] Yield: 3.24 g (75%)

1 H NMR (DMSO-d 6, ppm): 2.55 (1H); 2.65 (1H); 2.80-3.05 (4H); 3.35 (1H); 4.25-4.45 (4H); 4.58 (1H); 5.93 (1H); 7.19-7.30 (10H); 7.81 (1H); 8.10 (1H); 8.28 (1H); 12.65 (3H).

LC / MS (ESI): 560.1; (calculated ([M + H +]): 560.5).

The substituted anionic compound A7 (3.24 g) in acid form is suspended in 50 ml of water and 0.521M sodium hydroxide is added dropwise to pH 7.08. After lyophilization, the desired product is obtained as a white solid.

[000680] Yield: 3.53 g (97%) 1H NMR (MeOD-d4, ppm): 2.61 (1H); 2.70 (1H); 2.95 (2H); 3.15 (2H);

4.29 (1H); 4.42 (3H); 4.64 (1H); 7.10-7.30 (10H).

[000682] LC / MS (ESI): 560.2; (calculated ([M + 3H + -3Na +]): 559.4). Part A 'Synthesis of a Polyanionic Compound

Polyanionic Compound 1: Sodium Maltotriosemethylcarboxylate

[000683] To 8 g (143 mmol of hydroxyl functional groups) of maltotriose (CarboSynth) dissolved in water at 65 ° C. is added 0.6 g (16 mmol) of sodium borohydride. After stirring for 30 minutes, 28 g (238 mmol) of sodium boroacetate are added. To this solution are then added dropwise 24 ml of 10 N NaOH (240 mmol) and the mixture is heated at 65 ° C for 90 minutes. 16.6 g (143 mmol) of sodium chloroacetate are then added to the reaction medium as well as 14 ml of 10 N NaOH (140 mmol) dropwise. After heating for 1 hour, the mixture is diluted with water, neutralized with acetic acid and then purified by ultrafiltration on a PES membrane of 1 kDa against water. The compound concentration of the final solution is determined by dry extract, and then an acid / base assay in a 50/50 water / acetone (V / V) mixture is carried out to determine the degree of substitution of sodium methylcarboxylate.

[000684] According to the dry extract: [polyanionic compound 1] = 32.9 mg / g

[000685] According to the acid / base assay: the degree of substitution of sodium methylcarboxylates per saccharide unit is 1.65.

[000686] The polyanionic compounds are selected by measuring their dissociation constant with respect to the calcium ions and their property of not destabilizing the hexameric form of the insulin.

[000687] As regards the dissociation constant with respect to the calcium ions, it is determined as follows.

Solutions containing 2.5 mM CaCl ₂ , 150 mM NaCl and increasing concentrations of polyanionic compound (between 0 and 20 mM) are prepared. The potential of all these formulations is measured and the concentrations of free calcium ions in the determined formulations. After linearization by the Scatchard method, the dissociation constants are established. These data make it possible to compare the affinity of the different polyanionic compounds for Ca. Part B: Preparation of solutions

Bl. Novolog® rapid analogue insulin solution at 100 IU / mL

[000689] This solution is a commercial solution of insulin aspart of Novo

Nordisk sold as Novolog®. This product is a fast analog insulin.

B2. Humalog rapid analog insulin solution ⁹ to 100 IU / mL

[000690] This solution is a commercial solution of Eli Lilly lispro insulin sold under the name of Humalog®. This product is a fast analog insulin. B3. Human insulin solution Humulin® R at 100 IU / mL

This solution is a commercial solution of human insulin Eli Lilly sold under the name Humulin® R. This product is a human insulin composition.

B4. Apidra® rapid analogue insulin solution at 100 IU / mL

[000692] This solution is a commercial solution of insulin glulisin from Sanofi sold under the name of Apidra®. This product is a fast analog insulin.

BS. Preparation of a 1,188 M sodium citrate solution

The sodium citrate solution is obtained by solubilizing 9.0811 g of sodium citrate (30.9 mmol) in 25 ml of water in a volumetric flask. The pH is adjusted to 7.4 by adding 1 ml of HCl 1. The solution is filtered through 0.22 μm.

B7. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the substituted anionic compound Al and citrate

For a final volume of 100 ml of composition, with a weight ratio [Al substituted anionic compound] / [insulin lispro] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order

Freeze-dried compound (Al substituted anionic compound) 730 mg

Humalog® commercial solution 100 mL

1,188 M sodium citrate solution 783 pL

[000695] The final pH is adjusted to 7.4 + 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B8. Preparation of a human insulin solution at 100 IU / ml in the presence of the substituted anionic compound Al and citrate

[000697] For a final volume of 100 ml of composition, with a weight ratio [Al substituted anionic compound] / [human insulin] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order

Freeze-dried compound (Al substituted anionic compound) 730 mg

Humulin® R 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

[000698] The final pH is adjusted to 7.4 ± 0.4.

[000699] The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

09. Preparation of a solution of insulin aspart at 100 IU / ml in the presence of the substituted anionic compound Al and citrate

For a final volume of 100 ml of composition, with a weight ratio [Al substituted anionic compound] / [insulin aspart] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order

Freeze-dried compound (Al substituted anionic compound) 730 mg

Novolog® 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

[000701] The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

ORGANIC. Preparation of a solution of insulin glulisine at 100 IU / ml in the presence of the substituted anionic compound Al and citrate

For a final volume of 100 ml of composition, with a mass ratio [substituted anionic compound Al] / [insulin glulisine] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order

Freeze-dried compound (Al substituted anionic compound) 730 mg

Apidra® commercial solution 100 mL

1,188M sodium citrate solution 783 pL

[000704] The final pH is adjusted to 7.4 ± 0.4.

B12. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the substituted anionic compound A2 and citrate

For a final volume of 100 ml of composition, with a mass ratio [substituted anionic compound A2] / [insulin lispro] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order Lyophilized compound (substituted anionic compound A2) 730 mg

Humalog® commercial solution 100 mL

1,188 M sodium citrate solution 783 pL

The final pH is adjusted to 7.4 ± 0.4.

B13. Preparation of a human insulin solution at 100 IU / ml in the presence of the substituted anionic compound A2 and citrate

For a final volume of 100 ml of composition, with a mass ratio [substituted anionic compound A2] / [human insulin] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order

Lyophilized compound (substituted anionic compound A2) 730 mg

Humuîin® R commercial solution 100 mL

1,188 M sodium citrate solution 783 pL

[000710] The final pH is adjusted to 7.4 ± 0.4.

B14. Preparation of a solution of insulin aspart at 100 IU / ml in the presence of the substituted anionic compound A2 and citrate

For a final volume of 100 ml of composition, with a mass ratio [substituted anionic compound A2] / [insulin aspart] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order

Lyophilized compound (substituted anionic compound A2) 730 mg

Novolog® 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

The final pH is adjusted to 7.4 ± 0.4.

BIS. Preparation of a solution of insulin glulisine at 100 IU / mL in the presence of the substituted anionic compound A2 and citrate

For a final volume of 100 ml of composition, with a mass ratio [substituted anionic compound A2] / [insulin glulisine] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified in the table and in the following order

Lyophilized compound (substituted anionic compound A2) 730 mg

Apidra® commercial solution 100 mL 1,188M sodium citrate solution 783 μΙ_

The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B26. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the compound Al and the polyanionic compound 1

For a final volume of 100 mL of formulation, with a weight ratio [Al compound] / [polyanionic compound I] / [insulin lispro] of 2.0 / 2.0 / 1, the various reagents are added in the quantities specified below and in the following order:

Freeze-dried Al compound 730 mg

Polyanionic compound 1 lyophilized 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B27. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of compound Al and polyanionic compound 1.

For a final volume of 100 mL of formulation, with a [Al compound] / [polyanionic compound] / [insulin lispro] mass ratio of 2/4/1, the various reagents are added in the amounts specified herein. below:

Al compound in freeze-dried form 730 mg

Polyanionic compound 1 in freeze-dried form 1460 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B28. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the compound Al and the polyanionic compound 1

For a final volume of 100 mL of formulation, with a weight ratio [Al compound] / [polyanionic compound I] / [insulin lispro] of 2.0 / 5.5 / 1, the various reagents are added in the quantities specified below and in the following order:

Freeze-dried Al compound 730 mg

Polyanionic compound 1 lyophilized 2000 mg

Commercial solution Humalog® 100 IU / mL 100 mL The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or other salt compatible with an injectable formulation .

The final pH is adjusted to 7.4 ± 0.4.

B29. Preparation of a lispro insulin solution at 100 IU / ml in the presence of the compound A2 and the polyanionic compound 1

For a final volume of 100 mL of formulation, with a mass ratio [compound A2] / [polyanionic compound I] / [insulin lispro] of 2.0 / 2.0 / 1, the various reagents are added in the quantities specified below and in the following order:

Freeze-dried compound A2 730 mg

Polyanionic compound 1 lyophilized 730 mg

The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B30. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of compound A2 and polyanionic compound 1.

For a final volume of 100 mL of formulation, with a mass ratio [compound A2] / [polyanionic compound I] / [insulin lispro] of 2/4/1, the various reagents are added in the amounts specified herein. below:

A2 compound in freeze-dried form 730 mg

Polyanionic compound 1 in freeze-dried form 1460 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

[000734] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000735] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B31. Preparation of a lispro insulin solution at 100 IU / ml in the presence of the compound A2 and the polyanionic compound 1

For a final volume of 100 mL of formulation, with a mass ratio [compound A2] / [polyanionic compound I] / [insulin lispro] of 2.0 / 5.5 / 1, the various reagents are added in the quantities specified below and in the following order:

Freeze-dried compound A2 730 mg

Polyanionic compound 1 lyophilized 2000 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

[000737] The polyanionic compound 1 may be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

The final pH is adjusted to 7.4 ± 0.4.

B39. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the substituted anionic compound A5 and citrate

For a final volume of 100 mL of formulation, with a weight ratio [anionic compound substituted A5] / [insulin lispro] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the amounts specified below and in the following order:

Anionic compound substituted freeze-dried A5 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

1,188 M sodium citrate solution 783 pL

For the citrate, it is possible to use the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000742] The final pH is adjusted to 7.4 ± 0.4.

B40. Preparation of a human insulin solution at 100 IU / ml in the presence of the substituted anionic compound A5 and citrate

For a final volume of 100 mL of formulation, with an [A5 substituted anionic compound] / [human insulin] mass ratio of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified below and in the following order:

Anionic compound substituted freeze-dried A5 730 mg

Humulin ^® R 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

[000746] The final pH is adjusted to 7.4 ± 0.4.

[000747] The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B41. Preparation of a solution of aspart insulin at 100 IU / ml in the presence of the substituted anionic compound A5 and citrate

For a final volume of 100 mL of formulation, with a mass ratio [anionic compound substituted A5] / [insulin aspart] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified below and in the following order:

Anionic compound substituted freeze-dried A5 730 mg

Novolog ^® 100 mL commercial solution 1,188 M sodium citrate solution 783 pL

For the citrate, it is possible to use the acid form or the basic form in the form of a sodium salt, a potassium salt or another salt that is compatible with an injectable formulation.

[000750] The final pH is adjusted to 7.4 ± 0.4.

B42. Preparation of a solution of insulin glulisine at 100 IU / ml in the presence of the substituted anionic compound A5 and citrate

For a final volume of 100 mL of formulation, with an [A5 substituted anionic compound] / [insulin glulisine] mass ratio of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added to the quantities specified below and in the following order:

Anionic compound substituted freeze-dried A5 730 mg

Apidra ^® 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

The final pH is adjusted to 7.4 ± 0.4.

B43. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of compound A5 and polyanionic compound 1 For a final volume of 100 ml of formulation, with a mass ratio [compound A5] / [polyanionic compound] ] / [insulin lispro] 2.0 / 2.0 / 1, the various reagents are added in the amounts specified below and in the following order:

Lyophilized A5 compound 730 mg

Polyanionic compound 1 lyophilized 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation. The final pH is adjusted to 7.4 ± 0.4.

B44. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of compound A5 and polyanionic compound 1.

For a final volume of 100 mL of formulation, with a [compound A5] / [polyanionic compound] / [insulin lispro] mass ratio of 2/4/1, the various reagents are added in the amounts specified below. below:

Compound A5 in freeze-dried form 730 mg Polyanionic compound 1 in freeze-dried form 1460 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

The polyanionic compound 1 may be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μσι membrane and stored at 4 ° C.

B45. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the compound A5 and the polyanionic compound 1 [000764] For a final volume of 100 ml of formulation, with a mass ratio [compound A5] / [polyanionic compound] ] / [insulin lispro] 2.0 / 5.5 / 1, the various reagents are added in the amounts specified below and in the following order:

Lyophilized compound A5 730 mg Polyanionic compound 1 freeze-dried 2000 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

[000766] The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B47. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the substituted anionic compound A6 and citrate

For a final volume of 100 mL of formulation, with an [A6 substituted anionic compound] / [insulin lispro] mass ratio of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in quantities specified below and in the following order:

Lyophilized A6 substituted anionic compound 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

1,188 M sodium citrate solution 783 pL

[000770] The final pH is adjusted to 7.4 ± 0.4.

B48. Preparation of a human insulin solution at 100 IU / ml in the presence of the substituted anionic compound A6 and citrate

For a final volume of 100 mL of formulation, with a weight ratio [A6 substituted anionic compound] / [human insulin] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified below and in the following order:

Lyophilized A6 substituted anionic compound 730 mg

Humulin ^® R 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

[000774] The final pH is adjusted to 7.4 ± 0.4.

B49. Preparation of a solution of aspart insulin at 100 IU / ml in the presence of the substituted anionic compound A6 and citrate

For a final volume of 100 mL of formulation, with a weight ratio [anionic compound substituted A6] / [insulin aspart] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the amounts specified below and in the following order:

Lyophilized A6 substituted anionic compound 730 mg

Novolog ^® 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

The final pH is adjusted to 7.4 ± 0.4.

B50. Preparation of a solution of insulin glulisine at 100 IU / ml in the presence of the substituted anionic compound A6 and citrate

For a final volume of 100 mL of formulation, with a mass ratio [A6 substituted anionic compound] / [insulin glulisine] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified below and in the following order:

Lyophilized A6 substituted anionic compound 730 mg

Apidra ^® 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

The final pH is adjusted to 7.4 ± 0.4.

B51. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the compound A6 and the polyanionic compound 1

For a final volume of 100 mL of formulation, with a mass ratio [compound A6] / [polyanionic compound I] / [insulin lispro] of 2.0 / 2.0 / 1, the various reagents are added in the quantities specified below and in the following order:

Lyophilized A6 compound 730 mg Polyanionic compound 1 lyophilized 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

[000785] The polyanionic compound 1 may be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000786] The final pH is adjusted to 7.4 ± 0.4.

B-52. Preparation of an Iispro Insulin Solution at 100 IU / ml in the Presence of Compound A6 and Polyanionic Compound 1

For a final volume of 100 mL of formulation, with a [compound A6] / [polyanionic compound] / [insulin Iispro] mass ratio of 2/4/1, the various reagents are added in the amounts specified herein. below:

A6 compound in freeze-dried form 730 mg

Polyanionic compound 1 in freeze-dried form 1460 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

[000789] The polyanionic compound 1 can be used in the acid form or the basic form in the form of a sodium salt, a potassium salt or another salt compatible with an injectable formulation.

The final pH is adjusted to 7.4 ± 0.4.

B53. Preparation of an Iispro Insulin Solution at 100 IU / mL in the Presence of Compound A6 and Polyanionic Compound 1

For a final volume of 100 mL of formulation, with a mass ratio [compound A6] / [polyanionic compound I] / [insulin Iispro] of 2.0 / 5.5 / 1, the various reagents are added in the quantities specified below and in the following order:

Lyophilized A6 compound 730 mg

Polyanionic compound 1 freeze-dried 2000 mg Commercial solution Humalog ^® 100 IU / mL 100 mL The polyanionic compound 1 may be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

The final pH is adjusted to 7.4 ± 0.4.

B55. Preparation of a lspro insulin solution at 100 IU / ml in the presence of the substituted anionic compound A7 and citrate

For a final volume of 100 mL of formulation, with an [A7 substituted anionic compound] / [insulin lispro] mass ratio of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added to the quantities specified below and in the following order:

A7 substituted freeze-dried anionic compound 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

1,188 M sodium citrate solution 783 pL

[000798] The final pH is adjusted to 7.4 ± 0.4.

[000799] The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B56. Preparation of a human insulin solution at 100 IU / ml in the presence of the substituted anionic compound A7 and citrate

For a final volume of 100 mL of formulation, with a weight ratio [A7 substituted anionic compound] / [human insulin] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the quantities specified below and in the following order:

A7 substituted freeze-dried anionic compound 730 mg

Humulin® R commercial solution 100 mL Sodium citrate solution 1,188 M 783 pL

The final pH is adjusted to 7.4 ± 0.4.

FIRE I LLE OF REM PLACEM ENT (RULE 26) The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B57. Preparation of a solution of aspart insulin at 100 IU / ml in the presence of the substituted anionic compound A7 and citrate

For a final volume of 100 mL of formulation, with an [A7 substituted anionic compound] / [insulin aspart] mass ratio of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added to the quantities specified below and in the following order:

A7 substituted freeze-dried anionic compound 730 mg

Novolog ^® 100 mL commercial solution

1,188 M sodium citrate solution 783 pL

The final pH is adjusted to 7.4 ± 0.4.

B58. Preparation of a solution of insulin gluiisine at 100 IU / ml in the presence of the substituted anionic compound A7 and citrate

For a final volume of 100 mL of formulation, with an [A7 substituted anionic compound] / [insulin gluiisin] mass ratio of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in quantities specified below and in the following order:

Lyophilized A7 substituted anionic compound 730 mg Commercial solution Apidra ^® 100 mL

1,188 M sodium citrate solution 783 pL

[000810] The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B59. Preparation of a lispro insulin solution at 100 IU / ml in the presence of the compound A7 and the polyanionic compound 1

For a final volume of 100 mL of formulation, with a mass ratio [compound A7] / [polyanionic compound I] / [insulin lispro] of 2.0 / 2.0 / 1, the various reagents are added in the quantities specified below and in the following order:

Freeze-dried A7 compound 730 mg

Polyanionic compound 1 lyophilized 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or other salt compatible with an injectable formulation. .

The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μηΊ membrane and stored at 4 ° C.

B60. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of compound A7 and polyanionic compound 1.

For a final volume of 100 mL of formulation, with a mass ratio [compound A7] / [polyanionic compound I] / [insulin lispro] of 2/4/1, the various reagents are added in the amounts specified herein. below:

A7 compound in freeze-dried form 730 mg

Polyanionic compound 1 in freeze-dried form 1460 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

[000817] The polyanionic compound 1 can be used in the acid form or the basic form in the form of a sodium salt, a potassium salt or another salt compatible with an injectable formulation.

[000818] The final pH is adjusted to 7.4 ± 0.4.

The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B61. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the compound A6 and the polyanionic compound 1

For a final volume of 100 mL of formulation, with a mass ratio [compound A7] / [polyanionic compound 1] / [insulin lispro] of 2.0 / 5.5 / 1, the various Reagents are added in the amounts specified below and in the following order:

Freeze-dried A7 compound 730 mg

Polyanionic compound 1 freeze-dried 2000 mg Commercial solution Humalog® 100 IU / mL 100 mL

[000822] The final pH is adjusted to 7.4 ± 0.4.

B62. Preparation of a similar insulin solution (insulin lispro) at 200 IU / mL.

[000824] The commercial formulation of insulin lispro (Humalog ^®) was concentrated using centrifuge tubes AMICOIM Ultra-15 with a cut to 3 kDa. The amicon tubes were first rinsed with 12 mL deionized water. 12 ml of the commercial formulation was centrifuged for 35 minutes at 4000 g at 20 ° C. The volume of the retentate was measured and the concentration thus estimated. All the retentates were pooled and the overall concentration was estimated (> 200 IU / mL).

[000825] The concentration of this concentrated lispro insulin solution was adjusted to 200 IU / mL by the addition of insulin commercial formulation lispro (Humalog ^®). The concentrated insulin lispro formulation has the same excipient concentrations (m-cresol, glycerin, phosphate) as the commercial formulation at 100 IU / mL.

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B63. Preparation of a human insulin solution at 200 IU / mL.

[000827] The commercial formulation of human insulin (Humulin® R) was concentrated using AMICON Ultra-15 centrifuge tubes with a cutoff at 3 kDa. The amicon tubes were first rinsed with 12 mL deionized water. 12 ml of the commercial formulation was centrifuged for 35 minutes at 4000 g at 20 ° C. The volume of the retentate was measured and the concentration thus estimated. All the retentates were pooled and the overall concentration was estimated (> 200 IU / mL).

FIRE I LLE OF REM PLACEM ENT (RULE 26) The concentration of this concentrated human insulin solution was adjusted to 200 IU / ml by addition of the commercial formulation of human insulin (Humulin® R). The concentrated human insulin formulation has the same excipient concentrations (m-cresol, glycerin) as the commercial formulation at 100 IU / mL.

[000829] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μιτι membrane and stored at 4 ° C.

B64. Preparation of insulin aspart solution at 200 IU / mL.

[000830] The commercial insulin aspart formulation (Novolog®) was concentrated using ICON Ultra-15 centrifuge tubes with a 3 kDa cutoff. The amicon tubes were first rinsed with 12 mL deionized water. 12 ml of the commercial formulation was centrifuged for 35 minutes at 4000 g at 20 ° C. The volume of the retentate was measured and the concentration thus estimated. All the retentates were pooled and the overall concentration was estimated (> 200 IU / mL).

The concentration of this concentrated aspart insulin solution was adjusted to 200 IU / ml by addition of the commercial insulin aspart formulation (Novolog®). The concentrated aspartate insulin concentrate formulation has the same excipient concentrations (m-cresol, glycerin) as the commercial formulation at 100 IU / mL.

[000832] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B65. Preparation of an Insulin Glulisine Solution at 200 IU / mL

[000833] The commercial insulin glulisine formulation (Apidra®) was concentrated using AMICON Ultra -15 centrifuge tubes with a 3 kDa cutoff. The amicon tubes were first rinsed with 12 mL deionized water. 12 ml of the commercial formulation was centrifuged for 35 minutes at 4000 g at 20 ° C. The volume of the retentate was measured and the concentration thus estimated. All the retentates were pooled and the overall concentration was estimated (> 200 IU / mL).

The concentration of this concentrated insulin glulisine solution was adjusted to 200 IU / ml by addition of the commercial formulation of insulin glulisine (Apidra®). The concentrated insulin glulisine formulation has the same concentrations of excipients (m-cresol, NaCl, TRIS) as the commercial formulation at 100 IU / mL.

[000835] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B66. Preparation of a solution of human insulin, insulin lispro, insulin aspart or insulin giulisin at 300, 400 and 500 IU / mL.

[000836] Concentrated formulations of human insulin, insulin lispro, insulin aspart or insulin Giulisine 300 IU / mL, 400 IU / mL or 500 IU / mL (and at all intermediate concentrations) are prepared on the basis of the protocol of Example B65 relating to the preparation of an insulin solution Giulisine 200 IU / mL. The commercial insulin formulation is concentrated using AMICON Ultra-15 centrifuge tubes with a 3 kDa cutoff. The amicon tubes are first rinsed with 12 mL deionized water. 12 ml of the commercial formulation are centrifuged at 4000 g and 20 ° C. By adjusting the centrifugation time it is possible to adjust the final insulin concentration in the formulation. The volume of the retentate is measured and the concentration thus estimated. All the retentates are pooled and the overall concentration is estimated (> 300, 400 or 500 IU / mL).

The concentration of this concentrated insulin solution is adjusted to the desired concentration (eg 300 IU / mL, 400 IU / mL or 500 IU / mL) by addition of the insulin formulation (Humulin® R, Novolog® , Humalog® or Apidra®). The concentrated concentrated insulin formulation has the same excipient concentrations as the commercial formulation at 100 IU / mL.

367. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound Al and citrate.

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin lispro] of 2, the various reagents are mixed in the amounts specified below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound Al 1460 mg

Solution of sodium citrate at 1, 188 M 1566 pL

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B68. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound Ai and polyanionic compound 1.

For a final volume of 100 mL of formulation with a mass ratio [Al substituted anionic compound] / [polyanionic compound 1] / [insulin lispro] of 2/2/1, the various reagents are mixed in the amounts specified herein. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound Al 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg

[000842] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000843] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B69. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound Al and the polyanionic compound 1.

[000844] For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [polyanionic compound I] / [lispro insulin] 2/4/1, the various reagents are mixed in the amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound Al 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000845] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000846] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B70. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound Al and citrate.

[000847] For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [human insulin] of 2, the various reagents are mixed in the amounts specified below:

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 1460 mg

Sodium citrate solution at 1.188 M 1566 pL [000848] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B71. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound Al and the polyanionic compound 1

[000849] For a final volume of 100 ml of formulation with a weight ratio [Al substituted anionic compound] / [polyanionic compound 1] / [human insulin] of 2/2/1, the various reagents are mixed in the amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg

[000850] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B72. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound Al and the polyanionic compound 1

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [polyanionic compound I] / [human insulin] of 2/4/1, the various reagents are mixed in the amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000852] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000853] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B73. Preparation of an aspart insulin solution at 200 IU / ml in the presence of the substituted anionic compound A1 and citrate.

For a final volume of 100 ml of formulation with a weight ratio [Al substituted anionic compound] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilizate of the substituted anionic compound Al 1460 mg

Insulin aspart 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL [000855] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B74. Preparation of a solution of insulin glulisine at 200 IU / ml in the presence of the substituted anionic compound Al and citrate.

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin glulisine] of 2, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilizate of the substituted anionic compound Al 1460 mg

Insulin glulisine 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B75. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 ml of formulation with a weight ratio [substituted anionic compound A2] / [insulin lispro] of 2, the various reagents are mixed in the amounts specified below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A2 1460 mg

1,188 M sodium citrate solution 1566 pL

B76. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A2 and polyanionic compound 1.

For a final volume of 100 ml of formulation with a mass ratio [substituted anionic compound A2] / [polyanionic compound 1] / [insulin lispro] of 2/2/1, the various reagents are mixed in the amounts specified herein. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A2 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg

[000861] The polyanionic compound 1 may be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation. [000862] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μηη membrane and stored at 4 ° C.

B77. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A2 and the polyanionic compound 1.

For a final volume of 100 ml of formulation with a mass ratio [substituted anionic compound A2] / [polyanionic compound I] / [lispro insulin] of 2/4/1, the various reagents are mixed in the amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A2 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000864] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000865] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B78. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [human insulin] of 2, the various reagents are mixed in the amounts specified below:

Human Insulin 200 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 1460 mg

Sodium citrate solution at 1.188 M 1566 pL

[000867] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B79. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A2 and the polyanionic compound 1

For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [polyanionic compound I] / [human insulin] of 2/2/1, the various reagents are mixed in the amounts specified herein. below

Human Insulin 200 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg [000869] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B80. Preparation of a human insulin solution at 20Θ IU / ml in the presence of the substituted anionic compound A2 and the polyanionic compound i.

[000870] For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [polyanionic compound 1] / [human insulin] of 2/4/1, the various reagents are mixed in the amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000871] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000872] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B81. Preparation of an aspart insulin solution at 200 IU / ml in the presence of the substituted anionic compound A2 and citrate.

[000873] For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilisate of the substituted anionic compound A2 1460 mg

Insulin aspart 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

B82. Preparation of a solution of insulin glulisine at 200 IU / mL in the presence of the substituted anionic compound A2 and citrate.

[000875] For a final volume of 100 ml of formulation with a weight ratio [substituted anionic compound A2] / [insulin glulisine] of 2, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilisate of the substituted anionic compound A2 1460 mg

Insulin glulisine 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL [000876] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B99. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A5 and citrate.

[000877] For a final volume of 100 mL of formulation with an [A5 substituted anionic compound] / [insulin lispro] mass ratio of 2, the various reagents are mixed in the amounts specified below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 1460 mg

1,188 M sodium citrate solution 1566 pL

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B100. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A5 and polyanionic compound 1.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A5] / [polyanionic compound 1] / [insulin lispro] of 2/2/1, the various reagents are mixed in amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 1460 mg

Lyophilizate of polyanionic compound 1 1 460 mg

[000880] The polyanionic compound 1 may be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

BlOl. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A5 and of the polyanionic compound 1.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A5] / [polyanionic compound 1] / [insulin lispro] 2/4/1, the various reagents are mixed in amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg [000883] The polyanionic compound 1 can be used in the acid form or the basic form in the form of a sodium salt, a potassium salt or another salt compatible with an injectable formulation.

B102. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [A5 substituted anionic compound] / [human insulin] of 2, the various reagents are mixed in the amounts specified below:

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A5 1460 mg

Sodium citrate solution at 1.188 M 1566 pL

B103. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A5 and of the polyanionic compound 1

For a final volume of 100 mL of formulation with a weight ratio [anionic compound substituted A5] / [polyanionic compound 1] / [human insulin] of 2/2/1, the various reagents are mixed in the amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A5 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg

B104. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound AS and of the polyanionic compound 1

For a final volume of 100 mL of formulation with a mass ratio [A5 substituted anionic compound] / [polyanionic compound I] / [human insulin] of 2/4/1, the various reagents are mixed in the amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A5 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg [000890] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000891] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B105. Preparation of an aspart insulin solution at 200 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [anionic compound substituted A5] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilizate of the substituted anionic compound A5 1460 mg

Insulin aspart 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

[000893] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B106. Preparation of a solution of insulin glulisine at 200 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with an [A5 substituted anionic compound] / [insulin glulisine] mass ratio of 2, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilizate of the substituted anionic compound A5 1460 mg

Insulin glulisine 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

[000895] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B107. Preparation of a solution of Iispro insulin at 200 IU / ml in the presence of the substituted anionic compound A6 and citrate.

[000896] For a final volume of 100 mL of formulation with a mass ratio [A6 substituted anionic compound] / [Iispro insulin] of 2, the different reagents are mixed in the amounts specified below.

Insulin Iispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A6 1460 mg

1,188 M sodium citrate solution 1566 pL [000897] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

BIOS. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A6 and polyanionic compound 1.

[000898] For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A6] / [polyanionic compound 1] / [insulin lispro] of 2/2/1, the various reagents are mixed in amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A6 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg

[000899] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000900] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B109. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A6 and of the polyanionic compound 1.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A6] / [polyanionic compound 1] / [insulin lispro] 2/4/1, the various reagents are mixed in amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A6 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000902] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

B110. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [A6 substituted anionic compound] / [human insulin] of 2, the various reagents are mixed in the amounts specified below: Human Insulin 200 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 1460 mg

Sodium citrate solution at 1.188 M 1566 pL

Bill. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A6 and of the polyanionic compound 1

For a final volume of 100 mL of formulation with a weight ratio [anionic compound substituted A6] / [polyanionic compound 1] / [human insulin] of 2/2/1, the various reagents are mixed in amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg

B112. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A6 and of the polyanionic compound 1

For a final volume of 100 mL of formulation with a weight ratio [anionic compound substituted A6] / [polyanionic compound 1] / [human insulin] 2/4/1, the various reagents are mixed in amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000909] The polyanionic compound 1 can be used in the acid form or the basic form in the form of a sodium salt, a potassium salt or another salt compatible with an injectable formulation.

[000910] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B113. Preparation of an aspart insulin solution at 200 IU / ml in the presence of the substituted anionic compound A6 and citrate.

[000911] For a final volume of 100 mL of formulation with an [A6 substituted anionic compound] / [insulin aspart] mass ratio of 2.0, the various reagents are mixed in the amounts specified below and in the following order: Lyophilisate of the substituted anionic compound A6 1460 mg

Insulin aspart 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

B114. Preparation of a solution of insulin glulisine at 200 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [A6 substituted anionic compound] / [insulin glulisine] of 2, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilisate of the substituted anionic compound A6 1460 mg

Insulin glulisine 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

[000914] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

Bill. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[000915] For a final volume of 100 mL of formulation with an [A7 substituted anionic compound] / [insulin lispro] mass ratio of 2, the various reagents are mixed in the amounts specified below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A7 1460 mg

1,188 M sodium citrate solution 1566 pL

[000916] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B116. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A7 and of polyanionic compound 1.

For a final volume of 100 mL of formulation with a weight ratio [anionic compound substituted A7] / [polyanionic compound 1] / [insulin lispro] of 2/2/1, the various reagents are mixed in the amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg [000918] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

B117. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A7 and of the polyanionic compound 1.

For a final volume of 100 ml of formulation with a weight ratio [anionic compound substituted A7] / [polyanionic compound 1] / [insulin lispro] 2/4/1, the various reagents are mixed in the amounts specified below. below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A7 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000921] The polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000922] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B118. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A7 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [A7 substituted anionic compound] / [human insulin] of 2, the various reagents are mixed in the amounts specified below:

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A7 1460 mg

Sodium citrate solution at 1.188 M 1566 pL

[000924] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B119. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A7 and of the polyanionic compound 1

For a final volume of 100 mL of formulation with a weight ratio [anionic compound substituted A7] / [polyanionic compound 1] / [human insulin] of 2/2/1, the various reagents are mixed in the amounts specified below. below Human Insulin 200 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 1460 mg

Lyophilizate of polyanionic compound 1 1460 mg

B120. Preparation of a human insulin solution at 200 IU / ml in the presence of the substituted anionic compound A7 and of the polyanionic compound 1

For a final volume of 100 mL of formulation with a weight ratio [anionic compound substituted A7] / [polyanionic compound 1] / [human insulin] of 2/4/1, the various reagents are mixed in amounts specified below. below

Human Insulin 200 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A7 1460 mg

Lyophilizate of polyanionic compound 1 2920 mg

[000928] The polyanionic compound 1 may be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[000929] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B121. Preparation of an aspart insulin solution at 200 IU / ml in the presence of the substituted anionic compound A7 and citrate.

For a final volume of 100 mL of formulation with an [A7 substituted anionic compound] / [insulin aspart] mass ratio of 2.0, the various reagents are mixed in the amounts specified below and in the following order:

Lyophilizate of the substituted anionic compound A7 1460 mg

Insulin aspart 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

[000931] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B122. Preparation of a solution of insulin glulisine at 200 IU / mL in the presence of the substituted anionic compound A7 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [A7 substituted anionic compound] / [insulin glulisine] of 2, the various reagents are mixed in the amounts specified below and in the following order: Lyophilizate of the substituted anionic compound A7 1460 mg

Insulin glulisine 200 IU / mL 100 mL

Sodium citrate solution at 1.188 M 1566 pL

[000933] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B123. Preparation of an Iispro insulin solution at 300 IU / ml in the presence of the substituted anionic compound Al and citrate.

[000934] For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin Iispro] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin Iispro 300 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2190 mg

Sodium citrate 720 mg

[000935] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered 0.22 μm membrane and stored at 4 ° C.

B124. Preparation of a human insulin solution at 300 IU / ml in the presence of the substituted anionic compound A1 and citrate.

[000936] For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 300 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2190 mg

Sodium citrate 720 mg

[000937] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B125. Preparation of a solution of insulin glulisine at 300 IU / ml in the presence of the substituted anionic compound Al and citrate.

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin glulisine] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 300 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2190 mg

Sodium citrate 720 mg [000939] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B126. Preparation of a solution of insulin aspart at 300 IU / ml in the presence of the substituted anionic compound Al and citrate.

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin aspart 300 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2190 mg

Sodium citrate 720 mg

[000941] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B127. Preparation of a lispro insulin solution at 400 IU / ml in the presence of the substituted anionic compound A1 and citrate.

[000942] For a final volume of 100 mL of formulation with a mass ratio

[Al substituted anionic compound] / [insulin lispro] 2.0 The various reagents are mixed in the amounts specified below:

Insulin lispro 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2920 mg

Sodium citrate 960 mg

[000943] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B128. Preparation of a human insulin solution at 400 IU / ml in the presence of the substituted anionic compound A1 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2920 mg

Sodium citrate 960 mg

[000945] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B129. Preparation of a solution of insulin glulisine at 400 IU / ml in the presence of the substituted anionic compound Al and citrate.

[000946] For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin glulisine] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2920 mg

Sodium citrate 960 mg

[000947] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B130. Preparation of an aspart insulin solution at 400 IU / ml in the presence of the substituted anionic compound A1 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin aspart] of 2, the various reagents are mixed in the amounts specified below:

Insulin aspart 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound Al 2920 mg

Sodium citrate 960 mg

[000949] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B131. Preparation of a solution of insulin lispro at 500 IU / ml in the presence of the substituted anionic compound Al and citrate.

[000950] For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [insulin lispro] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro at 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound Al 3650 mg

Sodium citrate 1200 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B132. Preparation of a human insulin solution at 500 IU / ml in the presence of the substituted anionic compound Ai and citrate.

Human Insulin 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound Al 3650 mg

Sodium citrate 1200 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered 0.22 μπτι membrane and stored at 4 ° C.

B133. Preparation of a solution of insulin glulisine at 500 IU / ml in the presence of the substituted anionic compound Al and citrate.

Insulin glulisine 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound Al 3650 mg

Sodium citrate 1200 mg

B134. Preparation of a solution of aspart insulin at 500 IU / ml in the presence of the substituted anionic compound Al and citrate.

Insulin aspart 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound Al 3650 mg

Sodium citrate 1200 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μηι membrane and stored at 4 ° C. B135. Preparation of a solution of insulin lispro at 300 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 ml of formulation with a mass ratio [substituted anionic compound A2] / [insulin lispro] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro at 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 2190 mg

Sodium citrate 720 mg

B136. Preparation of a human insulin solution at 300 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 2190 mg

Sodium citrate 720 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered 0.22 μm membrane and stored at 4 ° C.

B137. Preparation of a solution of insulin glulisine at 300 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [insulin glulisine] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 2190 mg

Sodium citrate 720 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B138. Preparation of an insulin aspart solution at 300 IU / ml in the presence of the substituted anionic compound A2 and citrate.

[000964] For a final volume of 100 ml of formulation with a weight ratio [substituted anionic compound A2] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin aspart 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 2190 mg

Sodium citrate 720 mg

[000965] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μιτι membrane and stored at 4 ° C.

B139. Preparation of a solution of insulin lispro at 400 IU / ml in the presence of the substituted anionic compound A2 and citrate.

[000966] For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [insulin lispro] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A2 2920 mg

Sodium citrate 960 mg

[000967] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B140. Preparation of a human insulin solution at 400 IU / ml in the presence of the substituted anionic compound A2 and citrate.

Human Insulin 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A2 2920 mg

Sodium citrate 960 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μητι membrane and stored at 4 ° C. B141. Preparation of a solution of insulin glulisine at 400 IU / ml in the presence of the substituted anionic compound A2 and citrate.

[000970] For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [insulin glulisine] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A2 2920 mg

Sodium citrate 960 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered on a 0.22 μιη membrane and stored at 4 ° C.

B142. Preparation of an aspart insulin solution at 400 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [insulin aspart] of 2, the various reagents are mixed in the amounts specified below:

Insulin aspart 400 IU / mL 100 mL

Lyophilizate of the substituted anionic compound A2 2920 mg

Sodium citrate 960 mg

B143. Preparation of a solution of insulin lispro at 500 IU / ml in the presence of the substituted anionic compound A2 and citrate.

Insulin lispro at 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 3650 mg

Sodium citrate 1200 mg

[000975] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μιτι membrane and stored at 4 ° C. B144. Preparation of a human insulin solution at 500 IU / ml in the presence of the substituted anionic compound A2 and citrate.

Human Insulin 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 3650 mg

Sodium citrate 1200 mg

[000977] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B145. Preparation of a solution of insulin glulisine at 500 IU / ml in the presence of the substituted anionic compound A2 and citrate.

Insulin glulisine 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 3650 mg

Sodium citrate 1200 mg

B146. Preparation of an aspart insulin solution at 500 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [substituted anionic compound A2] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin aspart 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A2 3650 mg

Sodium citrate 1200 mg

[000981] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B171. Preparation of a solution of insulin lispro at 300 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with an [A5 substituted anionic compound] / [insulin lispro] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro at 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 2190 mg

Sodium citrate 720 mg

[000983] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B172. Preparation of a human insulin solution at 300 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [A5 substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 2190 mg

Sodium citrate 720 mg

[000985] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B173. Preparation of a solution of insulin glulisine at 300 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with an [A5 substituted anionic compound] / [insulin glulisine] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 2190 mg

Sodium citrate 720 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B174. Preparation of an insulin aspart solution at 300 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A5] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin aspart 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 2190 mg

Sodium citrate 720 mg

[000989] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B175. Preparation of a lispro insulin solution at 400 IU / ml in the presence of the substituted anionic compound A5 and citrate.

Insulin lispro 400 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 2920 mg

Sodium citrate 960 mg

B176. Preparation of a human insulin solution at 400 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [A5 substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 400 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 2920 mg

Sodium citrate 960 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B177. Preparation of a solution of insulin glulisine at 400 IU / ml in the presence of the substituted anionic compound A5 and citrate.

[000994] For a final volume of 100 mL of formulation with a mass ratio

[Substituted anionic compound A5] / [insulin glulisine] 2.0 The various reagents are mixed in the amounts specified below:

Insulin glulisine 400 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 2920 mg

Sodium citrate 960 mg

B178. Preparation of an aspart insulin solution at 400 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A5] / [insulin aspart] of 2, the various reagents are mixed in amounts specified below:

Insulin aspart 400 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 2920 mg

Sodium citrate 960 mg

B179. Preparation of a solution of Iispro insulin at 500 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [A5 substituted anionic compound] / [Iispro insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin Iispro 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 3650 mg

Sodium citrate 1200 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B180. Preparation of a human insulin solution at 500 IU / ml in the presence of the substituted anionic compound AS and citrate.

For a final volume of 100 mL of formulation with an [A5 substituted anionic compound] / [human insulin] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 3650 mg

Sodium citrate 1200 mg

[0001001] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B181. Preparation of a solution of insulin glulisine at 500 IU / ml in the presence of the substituted anionic compound A5 and citrate.

[0001002] For a final volume of 100 mL of formulation with an [A5 substituted anionic compound] / [insulin glulisine] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 3650 mg

Sodium citrate 1200 mg

[0001003] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B182. Preparation of a solution of aspart insulin at 500 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [A5 substituted anionic compound] / [insulin aspart] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin aspart 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A5 3650 mg

Sodium citrate 1200 mg

[0001005] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B183. Preparation of a solution of insulin lispro at 300 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with an [A6 substituted anionic compound] / [insulin lispro] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro at 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2190 mg

Sodium citrate 720 mg

[0001007] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μηπ membrane and stored at 4 ° C.

B184. Preparation of a human insulin solution at 300 IU / ml in the presence of the substituted anionic compound A6 and citrate.

[0001008] For a final volume of 100 mL of formulation with a weight ratio [A6 substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2190 mg

Sodium citrate 720 mg

[0001009] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B185. Preparation of a solution of insulin glulisine at 300 IU / ml in the presence of the substituted anionic compound A6 and citrate.

[0001010] For a final volume of 100 mL of formulation with an [A6 substituted anionic compound] / [insulin glulisine] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2190 mg

Sodium citrate 720 mg

[0001011] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B186. Preparation of an insulin aspart solution at 300 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with an [A6 substituted anionic compound] / [insulin aspart] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin aspart 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2190 mg

Sodium citrate 720 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μιτι membrane and stored at 4 ° C.

B187. Preparation of a lispro insulin solution at 400 IU / ml in the presence of the substituted anionic compound A6 and citrate.

Insulin lispro 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2920 mg

Sodium citrate 960 mg

[0001015] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B188. Preparation of a human insulin solution at 400 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [A6 substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2920 mg

Sodium citrate 960 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B189. Preparation of an insulin glulisine solution at 400 IU / ml in the presence of the substituted anionic compound A6 and citrate.

[0001018] For a final volume of 100 mL of formulation with a mass ratio

[A6 substituted anionic compound] / [insulin glulisine] 2.0 The various reagents are mixed in the amounts specified below:

Insulin glulisine 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2920 mg

Sodium citrate 960 mg

B190. Preparation of an aspart insulin solution at 400 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A6] / [insulin aspart] of 2, the various reagents are mixed in amounts specified below:

Insulin aspart 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 2920 mg

Sodium citrate 960 mg

[0001021] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered 0.22 μm membrane and stored at 4 ° C.

B191. Preparation of a solution of insulin lispro at 500 IU / ml in the presence of the substituted anionic compound A6 and citrate.

[0001022] For a final volume of 100 mL of formulation with an [A6 substituted anionic compound] / [insulin lispro] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro at 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 3650 mg

Sodium citrate 1200 mg

[0001023] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B192. Preparation of a human insulin solution at 500 IU / ml in the presence of the substituted anionic compound A6 and citrate.

[0001024] For a final volume of 100 mL of formulation with a weight ratio [A6 substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 3650 mg

Sodium citrate 1200 mg

[0001025] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B193. Preparation of a solution of insulin glulisine at 500 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with an [A6 substituted anionic compound] / [insulin glulisine] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 3650 mg

Sodium citrate 1200 mg

B194. Preparation of an aspart insulin solution at 500 IU / ml in the presence of the substituted anionic compound A6 and citrate.

Insulin aspart 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A6 3650 mg

Sodium citrate 1200 mg

[0001029] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B195. Preparation of a solution of insulin lispro at 300 IU / ml in the presence of the substituted anionic compound A7 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [A7 substituted anionic compound] / [insulin lispro] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro at 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2190 mg

Sodium citrate 720 mg

B196. Preparation of a human insulin solution at 300 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001032] For a final volume of 100 mL of formulation with a mass ratio [A7 substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2190 mg

Sodium citrate 720 mg

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered 0.22 μηπ membrane and stored at 4 ° C.

B197. Preparation of a solution of insulin glulisine at 300 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001034] For a final volume of 100 mL of formulation with a weight ratio [substituted anionic compound A7] / [insulin glulisine] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2190 mg

Sodium citrate 720 mg

[0001035] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B198. Preparation of a solution of insuiine aspart at 300 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001036] For a final volume of 100 mL of formulation with a mass ratio

[substituted anionic compound A7] / [insulin aspart] of 2.0 the various reagents are mixed in the amounts specified below:

Insulin aspart 300 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2190 mg

Sodium citrate 720 mg

[0001037] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B199. Preparation of a lispro insulin solution at 400 IU / ml in the presence of the substituted anionic compound A7 and citrate.

For a final volume of 100 mL of formulation with an [A7 substituted anionic compound] / [insulin lispro] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2920 mg

Sodium citrate 960 mg

B200. Preparation of a human insulin solution at 400 IU / ml in the presence of the substituted anionic compound A7 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [A7 substituted anionic compound] / [human insulin] of 2.0, the various reagents are mixed in the amounts specified below:

Human Insulin 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2920 mg

Sodium citrate 960 mg

[0001041] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B201. Preparation of a solution of insulin glulisine at 400 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001042] For a final volume of 100 mL of formulation with an [A7 substituted anionic compound] / [insulin glulisine] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2920 mg

Sodium citrate 960 mg

[0001043] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B202. Preparation of an aspart insulin solution at 400 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001044] For a final volume of 100 mL of formulation with a mass ratio [A7 substituted anionic compound] / [insulin aspart] of 2, the various reagents are mixed in the amounts specified below:

Insulin aspart 400 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 2920 mg

Sodium citrate 960 mg

[0001045] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C.

B203. Preparation of a solution of insulin lispro at 500 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001046] For a final volume of 100 mL of formulation with an [A7 substituted anionic compound] / [insulin lispro] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin lispro at 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 3650 mg

Sodium citrate 1200 mg

[0001047] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B204. Preparation of a human insulin solution at 500 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001048] For a final volume of 100 mL of formulation with a mass ratio

[A7 substituted anionic compound] / [human insulin] 2.0 The various reagents are mixed in the amounts specified below:

Human Insulin 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 3650 mg

Sodium citrate 1200 mg

[0001049] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μιτι membrane and stored at 4 ° C.

B20S. Preparation of a solution of insulin glulisine at 500 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001050] For a final volume of 100 mL of formulation with a weight ratio [substituted anionic compound A7] / [insulin glulisine] of 2.0, the various reagents are mixed in the amounts specified below:

Insulin glulisine 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 3650 mg

Sodium citrate 1200 mg

B206. Preparation of an aspart insulin solution at 500 IU / ml in the presence of the substituted anionic compound A7 and citrate.

[0001052] For a final volume of 100 ml of formulation with an [A7 substituted anionic compound] / [insulin aspart] mass ratio of 2.0, the various reagents are mixed in the amounts specified below:

Insulin aspart 500 IU / mL 100 mL

Lyophilisate of the substituted anionic compound A7 3650 mg

Sodium citrate 1200 mg

[0001053] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B207. Preparation of a solution of Iispro insulin at 200 IU / ml in the presence of the substituted anionic compound Al and citrate.

For a final volume of 100 mL of formulation with a weight ratio [Al substituted anionic compound] / [Iispro insulin] of 1, the various reagents are mixed in the amounts specified below.

Insulin Iispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound Al 730 mg

1,188 M sodium citrate solution 783 pL

B208. Preparation of a solution of Iispro insulin at 200 IU / ml in the presence of the substituted anionic compound A2 and citrate.

For a final volume of 100 mL of formulation with a weight ratio [substituted anionic compound A2] / [insulin Iispro] of 1, the various reagents are mixed in the amounts specified below.

Insulin Iispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A2 730 mg

1,188 M sodium citrate solution 783 pL

B211. Preparation of a solution of Iispro insulin at 200 IU / ml in the presence of the substituted anionic compound A5 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A5] / [insulin Iispro] of 1, the various reagents are mixed in the amounts specified below.

Insulin Iispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A5 730 mg

1,188 M sodium citrate solution 783 pL

The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B212. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A6 and citrate.

For a final volume of 100 mL of formulation with a mass ratio [anionic compound substituted A6] / [insulin lispro] of 1, the various reagents are mixed in the amounts specified below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A6 730 mg

1,188 M sodium citrate solution 783 pL

B213. Preparation of a solution of insulin lispro at 200 IU / ml in the presence of the substituted anionic compound A7 and citrate.

For a final volume of 100 mL of formulation with an [A7 substituted anionic compound] / [insulin lispro] mass ratio of 1, the various reagents are mixed in the amounts specified below.

Insulin lispro at 200 IU / mL 100 mL

Lyophilisate of substituted anionic compound A7 730 mg

1,188 M sodium citrate solution 783 pL

[00011]

C Pharmacodynamics and pharmacokinetics

Protocol for measuring the pharmacodynamics of insulin solutions

[0001054] Domestic pigs of about 50 kg, previously catheterized at the jugular, are fasted 2.5 hours before the start of the experiment. In the hour before the injection of insulin, 3 blood samples are taken to determine the basal level of glucose and insulin. [0001055] Insulin injection at a dose of 0.09 IU / kg for insulin lispro is performed subcutaneously in the neck, under the ear of the animal using a insulin pen (Novo, Sanofi or Lilly) equipped with a 31 G needle.

[0001056] Blood samples are then taken every 4 minutes for 20 minutes and then every 10 minutes up to 3 hours. After each sample, the catheter is rinsed with a dilute solution of heparin.

[0001057] A drop of blood is taken to determine the blood glucose by means of a glucometer.

[0001058] The glucose pharmacodynamics curves expressed in percent of the basal level are then plotted. The time required to reach the minimum level of glucose in the blood and 50% of the minimum blood glucose level for each pig are determined and reported as Tmin glucose and T50% Rmin glucose, respectively. The averages of Tmin glucose and T50% Rmin glucose are then calculated.

[0001059] The remaining blood is collected in a dry tube and is centrifuged to isolate the serum. The insulin levels in the serum samples are measured by ELISA sandwich enzyme immunoassay for each pig.

The pharmacokinetic curves expressed in basal level delta are then plotted. The time required to reach the maximum concentration and the time required to reach 50% of the maximum insulin concentration in the serum for each pig are determined and reported as Tmax insulin and T50% Cmax insulin, respectively. The averages of Tmax insulin and T50% Cmax insulin are then calculated. C2: Pharmacodynamic and Pharmacokinetic Results of the Insulin Solutions of Examples B2 and B12

The pharmacodynamic results obtained with the compositions described in Examples B2 and B12 are presented in FIG. 1. The analysis of these curves shows that the composition of Example B12 comprising the substituted anionic compound A2 and citrate as excipient (curve plotted with the squares corresponding to example B12, Tmin glucose = 42 ± 12 min and T50% Rmin glucose = 18 ± 4 min) makes it possible to obtain a faster action than that of the composition Humalog® commercial of Example B2 (curve plotted with the triangles corresponding to Example B2, Tmin glucose = 47 ± 11 min and T50% Rmin glucose = 26 ± 8 min).

The pharmacokinetic results obtained with the compositions described in Examples B2 and B12 are presented in FIG. 2. Analysis of these curves shows that the composition of Example B12 comprising the substituted anionic compound A2 and citrate as an excipient (curve plotted with the squares corresponding to example B12, Tmax insulin = 24 ± 18 min and T50% Cmax insulin = 6 ± 3 min) induces a faster absorption of insulin lispro than the commercial Humalog® composition of example B2 (curve plotted with the triangles corresponding to example B2, Tmax insulin = 23 ± 23 min and T50% Cmax insulin = 17 ± 22 min).

C3: Pharmacodynamic and Pharmacokinetic Results of the Insulin Solutions of Examples B2 and B7

The pharmacodynamic results obtained with the compositions described in Examples B2 and B7 are presented in FIG. 3. The analysis of these curves shows that the composition of Example B7 comprising the substituted anionic compound Al and citrate as excipient (curve plotted with the squares corresponding to Example B7, Tmin glucose = 48 ± 22 min and T50% Rmin Glucose = 17 ± 7 min) makes it possible to obtain a faster action than that of the commercial Humalog® composition. Example B2 (curve plotted with the triangles corresponding to Example B2, Tmin glucose = 47 ± 11 min and T50% Rmin glucose = 26 ± 8 min).

The pharmacokinetic results obtained with the compositions described in Examples B2 and B7 are presented in FIG. 4. The analysis of these curves shows that the composition of Example B7 comprising the substituted anionic compound Al and citrate as excipient (curve plotted with the squares corresponding to example B7, Tmax insulin = 20 ± 14 min and T50% Cmax insulin = 6 ± 3 min) induces a faster absorption of insulin lispro than the commercial composition Humalog® of l Example B2 (curve plotted with the triangles corresponding to Example B2, Tmax insulin = 23 ± 23 min and T50% Cmax insulin = 17 ± 22 min).

C3 ': Pharmacodynamic and Pharmacokinetic Results of Insulin Solutions of Examples B2 and B7

Compound

Number of

Example Anionic Insulin Excipient

substituted pigs

B2 lispro - 9

B7 lispro Al Citrate 9.3 mM 11 [0001064] The pharmacodynamic results obtained with the compositions described in Examples B2 and B7 are presented in FIG. 14. Analysis of these curves shows that the composition of Example B7 comprising the substituted anionic compound Al and citrate as excipient (curve plotted with squares corresponding to the example B7, glucose Tmin = 35 ± 10 min and T50% glucose Rmin = 14 ± 4 min) allows to obtain a more rapid action than the commercial composition Humalog ^® of Example B2 (curve plotted with the triangles corresponding to Example B2, Tmin glucose = 38 ± 8 min and T50% Rmin glucose = 18 ± 10 min).

The pharmacokinetic results obtained with the compositions described in Examples B2 and B7 are presented in FIG. 15. Analysis of these curves shows that the composition of Example B7 comprising the substituted anionic compound Al and citrate as excipient (curve plotted with the squares corresponding to example B7, Tmax insulin = 13 ± 6 min and T50% Cmax insulin = 5 ± 4 min) induces a faster absorption of insulin lispro than the commercial composition Humalog ^® of the Example B2 (curve plotted with the triangles corresponding to example B2, Tmax insulin = 19 ± 8 min and T50% Cmax insulin = 8 ± 4 min). C4: Pharmacodynamic and Pharmacokinetic Results of the Insulin Solutions of Examples B2 and B39

The pharmacodynamic results obtained with the compositions described in Examples B2 and B39 are presented in FIG. 7. The analysis of these curves shows that the composition of Example B39 comprising the substituted anionic compound A5 and citrate as excipient (curve plotted with squares corresponding to example B39, glucose Tmin = 51 ± 25 min and T50% glucose Rmin = 15 ± 7 min) allows to obtain a more rapid action than the commercial composition Humalog ^® of Example B2 (curve plotted with the triangles corresponding to Example B2, Tmin glucose = 46 ± 18 min and T50% Rmin glucose = 21 ± 6 min). The pharmacokinetic results obtained with the compositions described in Examples B2 and B39 are presented in FIG. 8. The analysis of these curves shows that the composition of Example B39 comprising the substituted anionic compound A5 and citrate as excipient (curve plotted with the squares corresponding to example B39, Tmax insulin = 13 ± 12 min and T50% Cmax insulin = 4 ± 3 min) induces a faster absorption of insulin lispro than the commercial composition Humalog ^® of the Example B2 (curve plotted with the triangles corresponding to Example B2, Tmax insulin = 22 ± 20 min and T50% Cmax insulin = 7 ± 4 min).

C5: Pharmacodynamic and Pharmacokinetic Results of the Insulin Solutions of Examples B2 and B47

[0001068] The pharmacodynamic results obtained with the compositions described in Examples B2 and B47 are presented in FIG. 9. The analysis of these curves shows that the composition of Example B47 comprising the substituted anionic compound A6 and citrate as excipient (curve plotted with squares corresponding to example B47, glucose Tmin = 34 ± 10 min and T50% glucose Rmin = 13 ± 3 min) allows to obtain a more rapid action than the commercial composition Humalog ^® of Example B2 (curve plotted with the triangles corresponding to Example B2, Tmin glucose = 46 ± 18 and T50% Rmin glucose = 21 ±

6 min).

The pharmacokinetic results obtained with the compositions described in Examples B2 and B47 are presented in FIG. 10. The analysis of these curves shows that the composition of Example B47 comprising the substituted anionic compound A6 and citrate as excipient (curve plotted with the squares corresponding to example B47, Tmax insulin = 11 ± 5 min and T50% Cmax insulin = 5 ± 3 min) induces a faster absorption of insulin lispro than the commercial composition Humalog ^® of the Example B2 (curve plotted with the triangles corresponding to example B2, Tmax insulin = 22 ± 20 min and T50% Cmax insulin =

7 ± 4 min). C6: Pharmacodynamic and Pharmacokinetic Results of the Insulin Solutions of Examples B2 and B55

[0001070] The pharmacodynamic results obtained with the compositions described in Examples B2 and B55 are presented in FIG. 11. Analysis of these curves shows that the composition of Example B55 comprising the substituted anionic compound A7 and citrate as excipient (curve plotted with squares corresponding to example B55, glucose Tmin = 34 ± 15 min and T50% glucose Rmin = 15 ± 4 min) allows to obtain a more rapid action than the commercial composition Humalog ^® of Example B2 (curve plotted with the triangles corresponding to Example B2, Tmin glucose = 46 ± 18 and T50% Rmin glucose = 21 ±

6 min).

The pharmacokinetic results obtained with the compositions described in Examples B2 and B55 are presented in FIG. 12. Analysis of these curves shows that the composition of Example B55 comprising the substituted anionic compound A7 and citrate as excipient (curve plotted with the squares corresponding to example B55, Tmax insulin = 13 ± 9 min and T50% Cmax insulin = 4 ± 3 min) induces a faster absorption of insulin lispro than the commercial composition Humalog ^® of the Example B2 (curve plotted with the triangles corresponding to example B2, Tmax insulin = 22 ± 20 min and T50% Cmax insulin =

7 ± 4 min).

D Circular Dichroism (CD)

[0001072] Circular dichroism is used to study the secondary and quaternary structure of insulin. Insulin monomers are organized into dimers and hexamers. Hexamer is the most physically and chemically stable form of insulin. The CD signal at 276 nm is characteristic of the hexameric form of insulin (hexameric signal around -300 °, dimer signal between -200 ° and -250 ° and monomer signal below -200 °). The loss of the CD signal at 276 nm is therefore characteristic of a destabilization of the hexamer in dimers or monomers. Dl. Impact of substituted anionic compound Al sut Se CD signal of human insulin at 276 nm

[0001073] The results obtained are presented in FIG. 5. This figure describes the ordinate CD signal at 276 nm (deg.cm ² .dmol ^"1 ) and on the abscissa:

A: rhINS (human insulin) (100 IU / ml)

B: rhINS / EDTA

C: rhINS / Citrate

D: rhINS / EDTA / Citrate

E: rhINS / Al compound (100 IU / ml / 7.3 mg / ml)

[0001074] EDTA and the EDTA / citrate combination have a very marked impact on the hexameric structure of human insulin (complete dissociation of hexamer into dimers). In contrast, citrate and the substituted anionic compound Al have no impact on the hexameric structure of human insulin. In contrast to EDTA, compositions based on the substituted anionic compound Al do not dissociate hexamer from human insulin.

D2. Impact of the substituted anionic compound A2 on the CD signal of human insulin at 276 nm

[0001075] The results obtained are presented in FIG. 6. This figure describes the CD signal at 276 nm (deg.cm ² .dmol ¹ ) as ordinate and on the abscissa:

F: rhINS (100 IU / ml)

G: rhINS / Compound A2 (100 IU / ml / 7.3 mg / ml)

[0001076] The substituted anionic compound A2 has no impact on the hexameric structure of human insulin. Unlike EDTA, the A2-substituted anionic compound composition does not dissociate hexamer from human insulin. D3 State of association of insulin lispro evaluated by circular dichroism in the presence of different substituted anionic compounds and citrate

[0001077] Circular dichroism makes it possible to study the secondary and quaternary structure of insulin. Insulin monomers are organized into dimers and hexamers. Hexamer is the most physically and chemically stable form of insulin. There are two hexameric forms, the R6 form and the T6 form. Lispro insulin has a strong signal at 240 nm characteristic of the hexameric form R6 (the most stable form). The loss of the signal at 240 nm is related to a destabilization of the hexamer R6. Preparation of a solution of sodium citrate at 1.010 M

A solution of sodium citrate is obtained by solubilizing 14.9077 g of sodium citrate (50.69 mmol) in 50 ml of water in a volumetric flask. The pH is adjusted to 7.4 by addition of 0.21 ml of HCl 1.

Preparation of lispro insulin solutions at 100 IU / mL in the presence of the substituted anionic compound and citrate

For a final volume of 100 mL of formulation, with a concentration of anionic compound substituted at 7.3 mg / mL and a concentration of 9.3 mM citrate, the various reagents are added in the amounts specified below. and in the following order:

Lyophilized substituted anionic compound 730 mg

Humalog ^® 100 IU / mL commercial solution 100 mL

Sodium citrate solution at 1.010 M 921 pL

For the citrate, it is possible to use the acid form or the basic form of sodium salt, potassium salt or another salt compatible with an injectable formulation.

[0001081] The final pH is adjusted to 7.4 ± 0.4

Preparation of the lispro insulin solution at 100 IU / ml in the presence of citrate

For a final volume of 100 mL of formulation, with a concentration of 9.3 mM citrate, the various compounds are added in the amounts specified below and in the following order:

Humalog® 100 IU / mL commercial solution 100 mL

Sodium citrate solution at 1.010 M 921 pL

[0001084] For citrate, the acid form or the basic form of sodium salt, potassium salt or another salt compatible with an injectable formulation may be used. The final pH is adjusted to 7.4 ± 0.4

The clear solution is filtered on a 0.22pm membrane and stored at 4 ° C. Preparation of the lispro insulin solution at 100 IU / mL in the presence of EDTA

[0001086] For a final volume of 100 mL of formulation, with a concentration of 0.3 mM EDTA, the various compounds are added in the amounts specified below and in the following order:

Humalog® 100 IU / mL commercial solution 100 mL

EDTA commercial solution at 0.5 M 60 pL

[0001087] The final pH is adjusted to 7.4 ± 0.4

The clear solution is filtered through a 0.22pm membrane and stored at 4 ° C.

[0001089] The results obtained are presented in FIG. 13. This figure describes the CD signal at 240 nm on the ordinate (deg.cm ² .dmo! ') And on the abscissa:

A: insulin lispro 100 IU / mL

B: insulin lispro + 7.3 mg / mL of substituted anionic compound Al + citrate at 9.3 mM

C: insulin lispro + 7.3 mg / mL of substituted anionic compound A2 + citrate at 9.3 mM

D: insulin lispro + 7.3 mg / mL of substituted anionic compound A5 + citrate at 9.3 mM

E: insulin lispro + 7.3 mg / mL of substituted anionic compound A6 + citrate at 9.3 mM

F: insulin lispro + 7.3 mg / mL of substituted anionic compound A7 + citrate at 9.3 mM

G: insulin lispro + EDTA 300 μΜ

H: insulin lispro + citrate at 9.3 mM

[0001090] EDTA completely destroys the R6 form of Lispro insulin. EDTA therefore has a marked effect on hexamer. In contrast, citrate alone and the substituted anionic / citrate compound mixture have no impact on the CD signal at 240 nm. These compounds therefore have no impact on the R6 structure of the hexamer and a fortiori on the hexameric structure.

Claims

A composition, in the form of an aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound of non-saccharide structure and at least one polyanionic compound different from said substituted anionic compound, characterized in that the substituted anionic compound meets in the following Formula I:

Formula I

in which :

E represents an at least divalent radical, comprising from 2 to 6 carbon atoms,

p being an integer from 1 to 3,

2. Composition according to claim 1, characterized in that the substituted anionic compound, when bisubstituted, is chosen from compounds of formula In which the radical -R- is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV:

Form IV

3 <r * t + q <12, a is 0 or 1 when R _qi, R _q, R and R _rl _r2 are independently of each other, selected from -H, -OH or -COOH ; 2 <q + r * t <12, a is 0 or 1, when the groups R _q1 , R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

1 <q + r * t <12, a is equal to 0 or 1, when the groups R _q i, R _q2 , R _r i and R _r2 are, independently of one another, chosen from -H, -OH, or -COOH and at least two R _q or R _{r groups} are -COOH.

3. Composition according to claim 1, characterized in that the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals having 3 to 12 carbon atoms of formula IV:

Form IV

3 <q + r * t <12, a is equal to 0 or 1, when the groups R _q , R _q2 , R and R _r2 are, independently of one another, chosen from -H, -OH or -COOH ; 2≤ q + r * T≤ 12, a is 0 or 1, when _q R i, R _q2, R _r and R i _r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

4. Composition according to claim 1, characterized in that the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals having 3 to 12 carbon atoms of formula IV ":

2 <q + r * t <11, a is 0 or 1, where the groups R _ql, _q2 R, R _r and R _r2 are independently of each other, selected from -H, -OH, -COOH ; 1 <q + r * t <11, a is equal to 0 or 1, when the groups R _q1, R _q2 , R _r1 and R _r2 are, independently of one another, chosen from -H, -OH, or - COOH and at least one R _q or R _r is -COOH.

If a = 0 then t = 0. When q> 1 and / or t> 1, then the R _ql and R _q2 and the R _ri and R _r2 are identical or different from one carbon to another.

5. Composition according to claim 1, characterized in that the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV ":

3 <q + r * t <12, a is 0 or 1, when the groups R _q1 , R _q2 , R _r1 and R _r2 are, independently of one another, selected from -H, -OH or - COOH; 2 <q + r * t <12, a is 0 or 1, when the groups R _q1> R _q2 , R _r i and R _r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R _q or R _r is -COOH.

6. Composition according to any one of the preceding claims, characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the AA radical is derived from an aromatic amino acid containing a phenyl or an indole, substituted or unsubstituted or an aromatic amino acid derivative having substituted or unsubstituted phenyl or indole. In particular, the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.

7. Composition according to any one of the preceding claims, characterized in that the substituted anionic compound is chosen from compounds of formula I in which the radical E is derived from an alkyl compound. linear or branched compound comprising at least two functions selected from the group consisting of -OH, -COOH, -NH ₂ .

8. Composition according to any one of the preceding claims, characterized in that the substituted anionic compound is chosen from the compounds of formula I in which n = 0 and corresponds to formula II: Formula II

In which

AA, F and R are the definitions given above,

1 <m <6.

9. Composition according to any one of claims 1 to 7, characterized in that the substituted anionic compound is chosen from the compounds of formula I in which m = 0 and re ond to formula III: n Formula III

In which :

AA, E, F ', F ", p and R are the definitions given above,

- 1 <n <6.

10. Composition according to any one of the preceding claims, characterized in that the molar ratios of substituted anionic compound / insulin are between 0.6 and 300.

11. Composition according to any one of the preceding claims, characterized in that the weight ratios substituted anionic compound / insulin are between 0.5 and 30.

12. Composition according to any one of the preceding claims, characterized in that the concentration of substituted anionic compound is between 1.8 and 100 mg / ml.

13. Composition according to any one of the preceding claims, characterized in that the insulin is human insulin selected from recombinant human insulins.

14. Composition according to any one of claims 1 to 12, characterized in that insulin is a similar insulin selected from the group consisting of insulin lispro (Humalog®), insulin aspart (Novolog®, Novorapid® ) and insulin glulisine (Apidra®).

15. Pharmaceutical composition comprising a composition according to any one of the preceding claims, characterized in that the insulin concentration is between 240 and 3000 μΜ (40 to 500 IU / mL).

16. Composition according to any one of the preceding claims, characterized in that the polyanionic compound is selected from the group consisting of polycarboxylic acids and their salts of Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ .

17. Composition according to any one of the preceding claims, characterized in that the polyanionic compound is an anionic molecule chosen from the group consisting of citric acid, aspartic acid, glutamic acid and malic acid. tartaric acid, succinic acid, adipic acid, oxalic acid, phosphate, polyphosphoric acids, such as triphosphate and their salts of Na, K ⁺ , Ca ⁺ or Mg ²⁺ .

18. Composition according to any one of the preceding claims, characterized in that the concentration of polyanionic compound is between 2 and 150 mM.

19. Composition according to any one of the preceding claims, characterized in that the substituted anionic compound corresponds to Formula I in which the radical AA is derived from phenylalanine, and the radical R, comprising 3 to 12 carbon atoms, is from tartaric acid, succinic acid or an amino acid selected from aspartic acid and glutamic acid, especially the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid or succinic acid, and in particular n = 0 and m = 1.

20. Composition according to any one of claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical AA is derived from phenylalanine, and the radical R, comprising 3 to 12 carbon atoms. , is derived from succinic acid, tartaric acid or an amino acid selected from aspartic acid and glutamic acid, n = 0 and m = 1.

21. Composition according to any one of Claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical AA is derived from phenylalanine, n = 0, m = 1, the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid or succinic acid, in particular tartaric acid, and carries an acid function.

22. Composition according to any one of Claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the AA radical is derived from phenylalanine, m = 0, n = 1, p = 3, and E is from TRIS.

23. Composition according to any one of claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical

AA is derived from phenylalanine, m = 0, n = 1, p = 2, and E is derived from aspartic acid or glutamic acid.

Composition according to any one of Claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical

AA is derived from phenylalanine, m = 0, n = 1, 2 or 3, especially n = 3, p = 2, and E is derived from aspartic acid or glutamic acid.

24. Composition according to any one of Claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from succinic acid and comprises a carboxylic acid, m = 0, n = 1, p = 3, E is derived from TRIS, F 'is an amide function, the AA radical is derived from phenylalanine, and F "is a carbamate function.

25. Composition according to any one of claims 1 to 15, characterized in that the substituted anionic compound corresponds to formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from succinic acid and comprises a carboxylic acid, m = 0, n = 1, p = 3, E is derived from TRIS, F is an amide function, the AA radical is derived from phenylalanine, and F "is a urea function.

26. Composition according to any one of claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid and comprises a carboxylic acid, m = 1, n = 0, F is an amide function, and the AA radical is derived from phenylalanine.

27. Composition according to any one of claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from succinic acid and comprises a carboxylic acid, m = 1, n = 0, F is an amide function, and the AA radical is derived from phenylalanine.

28. Composition according to any one of Claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid and comprises a carboxylic acid, m = 0, n = 1, p = 3, E is derived from TRIS, F 'is an amide function, the AA radical is derived from phenylalanine, and F "is a carbamate function.

29. Composition according to any one of Claims 1 to 15, characterized in that the substituted anionic compound corresponds to Formula I in which the radical R, comprising 3 to 12 carbon atoms, is derived from tartaric acid and comprises a carboxylic acid, m = 0, n = 1, p = 2, E is derived from aspartic acid, F 'is an amide function, the AA radical is derived from phenylalanine, and F "is an amide function.

30. Substituted anionic compound, characterized in that it corresponds to the following Formula I:

Formula I

in which :

said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt chosen from Na ⁺ and K ⁺ ,

excluding compounds in which m = 2 and n = 0 and R carrying a carboxylic acid function and an alcohol function

31. Substituted anionic compound, characterized in that it corresponds to the following Formula I:

Formula I

in which :

R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 6 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions,

AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function, E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms, F, F ', F "represent, independently of each other, a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of a AA radical, F 'being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E, p being an integer between 1 and 3,

32. Substituted anionic compound, characterized in that it corresponds to the following Formula I:

Formula I

in which :

AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function, E represents a radical derived from Tris,

p being an integer from 1 to 3,

m is an integer from 0 to 6; n is an integer from 1 to 6; m + n is an integer from 1 to 6; said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na ⁺ and K ⁺ .

33. Substituted anionic compound, characterized in that it corresponds to the following Formula I:

Formula I

in which :

R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 3 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions;

AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function, E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms,

F is a function chosen from amide, carbamate or urea functions, and resulting from a reaction involving the amine of the aromatic amino acid, precursor of the AA radical, and a reactive function of the precursor of R,

F 'is an amide function involving a reactive function of the precursor R and a reactive function of the precursor of E,

F "is a carbamate function resulting from a reaction involving the amine of the aromatic amino acid, precursor of the AA radical, and a reactive function of the precursor of E,

p being an integer from 1 to 3,

said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na + and K +.